Abstract:

The instant invention provides for substituted naphthyridine compounds
that inhibit Akt activity. In particular, the compounds disclosed
selectively inhibit one or two of the Akt isoforms, preferably Akt1. The
invention also provides for compositions comprising such inhibitory
compounds and methods of inhibiting Akt activity especially Akt1 by
administering the compound to a patient in need of treatment of cancer.

Claims:

1. A compound according to Formula A: ##STR00064## wherein: E, F, G, H,
I, J, K, L and M are independently selected from: C or N, wherein each E,
F, G, H, I, J, K, L and M is optionally substituted with R1; a is 0
or 1; b is 0 or 1; m is 0, 1 or 2; p is independently 0, 1, 2, 3, 4 or 5;
Ring Y is (C4-C7)cycloalkyl, said cycloalkyl is substituted
with Rx, and further optionally substituted with one or more
substituents selected from: (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, CO2H, halo,
CN, OH and NR7R8, said alkyl, cycloalkyl and alkoxy is
optionally substituted with one or more substituents selected from halo,
CN, OH and NR7R8; Ring Z is selected from:
(C3-C8)cycloalkyl, aryl, heteroaryl and heterocyclyl; R1
is selected from: H, oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl,
(C═O)aOb(C2-C10)alkenyl,
(C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH,
Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8,
CN, (C═O)aOb(C3-C8)cycloalkyl,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl and
(C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl is optionally substituted with one or more
substituents selected from R6; R2 is independently selected
from: oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl,
(C═O)aOb(C2-C10)alkenyl,
(C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH,
Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8,
CN, (C═O)aOb(C3-C8)cycloalkyl, SH,
S(O)mNR7R8, S(O)m--(C1-C10)alkyl and
(C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl is optionally substituted with one or more
substituents selected from R6; R6 is:
(C═O)aOb(C1-C10)alkyl,
(C═O)aObaryl, (C2-C10)alkenyl,
(C2-C10)alkynyl, (C═O)aOb heterocyclyl,
CO2H, halo, CN, OH, Ob(C1-C6)perfluoroalkyl,
Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl or
(C═O)aOb(C3-C8)cycloalkyl, said alkyl, aryl,
alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted
with one or more substituents selected from R6a; R6a is
selected from: (C═O)aOb(C1-C10)alkyl,
Oa(C1-C3)perfluoroalkyl,
(C0-C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN,
(C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C0-C6)alkylene-aryl,
(C0-C6)alkylene-heterocyclyl,
(C0-C6)alkylene-N(Rb)2, C(O)Ra,
(C0-C6)alkylene-CO2Ra, C(O)H, and
(C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to
three substituents selected from Rb, OH, (C1-C6)alkoxy,
halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl,
oxo, and N(Rb)2; R7 and R8 are independently selected
from: H, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a; Ra is
(C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or
heterocyclyl; Rb is independently: H, (C1-C6)alkyl, aryl,
heterocyclyl, (C3-C6)cycloalkyl,
(C═O)aOb(C1-C6)alkyl, or S(O)mRa; and
Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; or a pharmaceutically acceptable
salt or a stereoisomer thereof.

2. A compound according to claim 1 of Formula A, wherein: ##STR00065##
is selected from: ##STR00066## ##STR00067## ##STR00068## Bond: is a
single or double bond, provided that when R1 is oxo, then said bond
is a single bond and adjacent N bears H; and all other substituents and
variables are as defined in claim 1; or a pharmaceutically acceptable
salt or a stereoisomer thereof.

3. A compound according to claim 2 of Formula B: ##STR00069## wherein:
Ring Y is cyclobutyl, said cyclobutyl is substituted with Rx, and
further optionally substituted with one or more substituents selected
from: (C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, CO2H, halo, CN, OH and NR7R8,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; p is 0,
1 or 2; R2 is independently selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, CO2H, halo, OH and NH2; and all other
substituents and variables are as defined in claim 2; or a
pharmaceutically acceptable salt or a stereoisomer thereof.

4. A compound according to claim 1 of Formula C: ##STR00070## wherein:
a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; R2 is
independently selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, CO2H, halo, OH and NH2; R1 is
selected from: H, oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl,
(C═O)aOb(C2-C10)alkenyl,
(C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH,
Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8,
CN, (C═O)aOb(C3-C8)cycloalkyl,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl and
(C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl is optionally substituted with one or more
substituents selected from R6; R6 is:
(C═O)aOb(C1-C10)alkyl,
(C═O)aObaryl, (C2-C10)alkenyl,
(C2-C10)alkynyl, (C═O)aOb heterocyclyl,
CO2H, halo, CN, OH, Ob(C1-C6)perfluoroalkyl,
Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl or
(C═O)aOb(C3-C8)cycloalkyl, said alkyl, aryl,
alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted
with one or more substituents selected from R6a; R6a is
selected from: (C═O)aOb(C1-C10)alkyl,
Oa(C1-C3)perfluoroalkyl,
(C0-C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN,
(C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C0-C6)alkylene-aryl,
(C0-C6)alkylene-heterocyclyl,
(C0-C6)alkylene-N(Rb)2, C(O)Ra,
(C0-C6)alkylene-CO2Ra, C(O)H, and
(C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to
three substituents selected from Rb, OH, (C1-C6)alkoxy,
halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl,
oxo, and N(Rb)2; R7 and R8 are independently selected
from: H, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a; Ra is
(C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or
heterocyclyl; and Rb is independently: H, (C1-C6)alkyl,
aryl, heterocyclyl, (C3-C6)cycloalkyl,
(C═O)aOb(C1-C6)alkyl, or S(O)mRa;
Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; Ry is selected from: H,
(C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, halo, CN and OH, said alkyl, cycloalkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; and Bond: is a single or double
bond, provided that when R1 is oxo, then said bond is a single bond
and adjacent N bears H; or a pharmaceutically acceptable salt or a
stereoisomer thereof.

5. A compound according to claim 1 of Formula D: ##STR00071## wherein:
a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; R2 is
independently selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, CO2H, halo, OH and NH2; R1 is
selected from: H, oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl,
(C═O)aOb(C2-C10)alkenyl,
(C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH,
Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8,
CN, (C═O)aOb(C3-C8)cycloalkyl,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl and
(C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl is optionally substituted with one or more
substituents selected from R6; R6 is:
(C═O)aOb(C1-C10)alkyl,
(C═O)aObaryl, (C2-C10)alkenyl,
(C2-C10)alkynyl, (C═O)aOb heterocyclyl,
CO2H, halo, CN, OH, Ob(C1-C6)perfluoroalkyl,
Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8,
S(O)mNR7R8, SH, S(O)m(C1-C10)alkyl or
(C═O)aOb(C3-C8)cycloalkyl, said alkyl, aryl,
alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted
with one or more substituents selected from R6a; R6a is
selected from: (C═O)aOb(C1-C10)alkyl,
Oa(C1-C3)perfluoroalkyl,
(C0-C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN,
(C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C0-C6)alkylene-aryl,
(C0-C6)alkylene-heterocyclyl,
(C0-C6)alkylene-N(Rb)2, C(O)Ra,
(C0-C6)alkylene-CO2Ra, C(O)H, and
(C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to
three substituents selected from Rb, OH, (C1-C6)alkoxy,
halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl,
oxo, and N(Rb)2; R7 and R8 are independently selected
from: H, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a; Ra is
(C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or
heterocyclyl; and Rb is independently: H, (C1-C6)alkyl,
aryl, heterocyclyl, (C3-C6)cycloalkyl,
(C═O)aOb(C1-C6)alkyl, or S(O)mRa;
Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; Ry is selected from: H,
(C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, halo, CN and OH, said alkyl, cycloalkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; and Bond: is a single or double
bond, provided that when R1 is oxo, then said bond is a single bond
and adjacent N bears H; or a pharmaceutically acceptable salt or a
stereoisomer thereof.

6. A compound according to claim 1 of Formula E: ##STR00072## wherein:
a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is 0, 1 or 2; R2 is
independently selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, CO2H, halo, OH and NH2; R1 is
selected from: H, oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl,
(C═O)aOb(C2-C10)alkenyl,
(C═O)aOb(C2-C10)alkynyl, CO2H, halo, OH,
Ob(C1-C6)perfluoroalkyl, (C═O)aNR7R8,
CN, (C═O)aOb(C3-C8)cycloalkyl,
S(O)mNR7R8, SH, S(O)m--(C1-C10)alkyl and
(C═O)aOb-heterocyclyl, said alkyl, aryl, alkenyl, alkynyl,
cycloalkyl, and heterocyclyl is optionally substituted with one or more
substituents selected from R6; R6 is:
(C═O)aOb(C1-C10)alkyl,
(C═O)aObaryl, (C2-C10)alkenyl,
(C2-C10)alkynyl, (C═O)aOb heterocyclyl,
CO2H, halo, CN, OH, Ob(C1-C6)perfluoroalkyl,
Oa(C═O)bNR7R8, oxo, CHO, (N═O)R7R8,
S(O)mNR7R8, SH, S(O)m(C1-C10)alkyl or
(C═O)aOb(C3-C8)cycloalkyl, said alkyl, aryl,
alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted
with one or more substituents selected from R6a; R6a is
selected from: (C═O)aOb(C1-C10)alkyl,
Oa(C1-C3)perfluoroalkyl,
(C0-C6)alkylene-S(O)mRa, SH, oxo, OH, halo, CN,
(C2-C10)alkenyl, (C2-C10)alkynyl,
(C3-C6)cycloalkyl, (C0-C6)alkylene-aryl,
(C0-C6)alkylene-heterocyclyl,
(C0-C6)alkylene-N(Rb)2, C(O)Ra,
(C0-C6)alkylene-CO2Ra, C(O)H, and
(C0-C6)alkylene-CO2H, said alkyl, alkenyl, alkynyl,
cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to
three substituents selected from Rb, OH, (C1-C6)alkoxy,
halogen, CO2H, CN, Oa(C═O)b(C1-C6)alkyl,
oxo, and N(Rb)2; R7 and R8 are independently selected
from: H, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a; Ra is
(C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, or
heterocyclyl; and Rb is independently: H, (C1-C6)alkyl,
aryl, heterocyclyl, (C3-C6)cycloalkyl,
(C═O)aOb(C1-C6)alkyl, or S(O)mRa;
Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; Ry is selected from: H,
(C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, halo, CN and OH, said alkyl, cycloalkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; and Bond: is a single or double
bond, provided that when R1 is oxo, then said bond is a single bond
and adjacent N bears H; or a pharmaceutically acceptable salt or a
stereoisomer thereof.

7. A compound according to claim 1 of Formula C-1: ##STR00073##
wherein: R1 is imidazolyl, triazolyl, or pyrimidyl, said imidazolyl,
triazolyl, and pyrimidyl is optionally substituted with one or more
(C1-C6)alkyl; R7 and R8 are independently selected
from: H, and (C1-C6)alkyl; Rx is selected from:
(C1-C6)alkyl, (C1-C6)alkoxy, halo, OH and
NR7R8, said alkyl, and alkoxy is optionally substituted with
one or more substituents selected from halo, CN, OH and NR7R8;
Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and
Bond: is a single or double bond, provided that when R1 is oxo,
then said bond is a single bond and adjacent N bears H; or a
pharmaceutically acceptable salt thereof.

8. A compound according to claim 1 of Formula D-1: ##STR00074##
wherein: R1 is pyridyl, said pyridyl is optionally substituted with
one or more (C1-C6)alkyl; R7 and R8 are independently
selected from: H, and (C1-C6)alkyl; Rx is selected from:
(C1-C6)alkyl, (C1-C6)alkoxy, halo, OH and
NR7R8, said alkyl, and alkoxy is optionally substituted with
one or more substituents selected from halo, CN, OH and NR7R8;
Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and
Bond: is a single or double bond, provided that when R1 is oxo,
then said bond is a single bond and adjacent N bears H; or a
pharmaceutically acceptable salt or a stereoisomer thereof.

9. A compound according to claim 1 of Formula D-1: ##STR00075##
wherein: R1 is (C1-C6)alkyl, NR7R8, phenyl,
pyridyl, pyrimidyl, pyrazinyl, azetidinyl, piperidinyl, or morpholinyl,
said alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, azetidinyl,
piperidinyl, and morpholinyl is optionally substituted with one or more
substituents selected from: (C1-C6)alkyl, halo, OH, and
NR7R8, said alkyl is optionally substituted with one or more
substituents selected from: halo, and OH; R7 and R8 are
independently selected from: H, and (C1-C6)alkyl; Rx is
selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halo, OH
and NR7R8, said alkyl, and alkoxy is optionally substituted
with one or more substituents selected from halo, CN, OH and
NR7R8; Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and
Bond: is a single or double bond, provided that when R1 is oxo,
then said bond is a single bond and adjacent N bears H; or a
pharmaceutically acceptable salt or a stereoisomer thereof.

10. A compound according to claim 1 of Formula E-1: ##STR00076##
wherein: R1 is pyrimidyl, said pyrimidyl is optionally substituted
with one or more (C1-C6)alkyl; R7 and R8 are
independently selected from: H, and (C1-C6)alkyl; Rx is
selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halo, OH
and NR7R8, said alkyl, and alkoxy is optionally substituted
with one or more substituents selected from halo, CN, OH and
NR7R8; Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and
Bond: is a single or double bond, provided that when R1 is oxo,
then said bond is a single bond and adjacent N bears H; or a
pharmaceutically acceptable salt or a stereoisomer thereof.

12. A pharmaceutical composition comprising a pharmaceutical carrier, and
dispersed therein, a therapeutically effective amount of a compound of
claim 1.

13. (canceled)

Description:

BACKGROUND OF THE INVENTION

[0001] The present invention relates to substituted naphthyridine
compounds which are inhibitors of the activity of one or more of the
isoforms of the serine/threonine kinase, Akt (also known as PKB;
hereinafter referred to as "Akt"). The present invention also relates to
pharmaceutical compositions comprising such compounds and methods of
using the instant compounds in the treatment of cancer.

[0002] Apoptosis (programmed cell death) plays essential roles in
embryonic development and pathogenesis of various diseases, such as
degenerative neuronal diseases, cardiovascular diseases and cancer.
Recent work has led to the identification of various pro- and
anti-apoptotic gene products that are involved in the regulation or
execution of programmed cell death. Expression of anti-apoptotic genes,
such as Bcl2 or Bcl-xL, inhibits apoptotic cell death induced by various
stimuli. On the other hand, expression of pro-apoptotic genes, such as
Bax or Bad, leads to programmed cell death (Adams et al. Science,
281:1322-1326 (1998)). The execution of programmed cell death is mediated
by caspase-1 related proteinases, including caspase-3, caspase-7,
caspase-8 and caspase-9 etc (Thornberry et al. Science, 281:1312-1316
(1998)).

[0004] Three members of the Akt subfamily of second-messenger regulated
serine/threonine protein kinases have been identified and termed
Akt1/PKBα, Akt2/PKBβ, and Akt3/PKBγ (hereinafter
referred to as "Akt1", "Akt2" and "Akt3"), respectively. The isoforms are
homologous, particularly in regions encoding the catalytic domains. Akts
are activated by phosphorylation events occurring in response to PI3K
signaling. PI3K phosphorylates membrane inositol phospholipids,
generating the second messengers phosphatidyl-inositol
3,4,5-trisphosphate and phosphatidylinositol 3,4-bisphosphate, which have
been shown to bind to the PH domain of Akt. The current model of Akt
activation proposes recruitment of the enzyme to the membrane by
3'-phosphorylated phosphoinositides, where phosphorylation of the
regulatory sites of Akt by the upstream kinases occurs (B. A. Hemmings,
Science 275:628-630 (1997); B. A. Hemmings, Science 276:534 (1997); J.
Downward, Science 279:673-674 (1998)).

[0008] These observations demonstrate that the PI3K/Akt pathway plays
important roles for regulating cell survival or apoptosis in
tumorigenesis.

[0009] Inhibition of Akt activation and activity can be achieved by
inhibiting PI3K with inhibitors such as LY294002 and wortmannin. However,
PI3K inhibition has the potential to indiscriminately affect not just all
three Akt isozymes but also other PH domain-containing signaling
molecules that are dependent on PdtIns(3,4,5)--P3, such as the Tec family
of tyrosine kinases. Furthermore, it has been disclosed that Akt can be
activated by growth signals that are independent of PI3K.

[0010] Alternatively, Akt activity can be inhibited by blocking the
activity of the upstream kinase PDK1. No specific PDK1 inhibitors have
been disclosed. Again, inhibition of PDK1 would result in inhibition of
multiple protein kinases whose activities depend on PDK1, such as
atypical PKC isoforms, SGK, and 56 kinases (Williams et al. Curr. Biol.
10:439-448 (2000).

[0013] The compounds of the instant invention have unexpected advantageous
properties over the cyclopropyl substituted naphthyridine compounds
specifically described in WO 2006/135627.

[0014] It is an object of the instant invention to provide novel compounds
that are inhibitors of Akt, especially Akt1.

[0015] It is also an object of the present invention to provide
pharmaceutical compositions that comprise the novel compounds that are
inhibitors of Akt, especially Akt1.

[0016] It is also an object of the present invention to provide a method
for treating cancer that comprises administering such inhibitors of Akt
activity, especially Akt1.

SUMMARY OF THE INVENTION

[0017] The instant invention provides for substituted naphthyridine
compounds that inhibit Akt activity. In particular, the compounds
disclosed selectively inhibit one or two of the Akt isoforms, preferably
Akt1. The invention also provides for compositions comprising such
inhibitory compounds and methods of inhibiting Akt activity, especially
Akt1 by administering the compound to a patient in need of treatment of
cancer.

DETAILED DESCRIPTION OF THE INVENTION

[0018] The compounds of the instant invention are useful in the inhibition
of the activity of the serine/threonine kinase Akt, especially Akt1. In a
first embodiment of this invention, the inhibitors of Akt activity are
illustrated by the Formula A:

[0020] a is 0 or 1; b is 0 or 1; m is 0, 1 or 2; p is independently 0, 1,
2, 3, 4 or 5;

[0021] Ring Y is (C4-C7)cycloalkyl, said cycloalkyl is
substituted with Rx, and further optionally substituted with one or
more substituents selected from: (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, CO2H, halo,
CN, OH and NR7R8, said alkyl, cycloalkyl and alkoxy is
optionally substituted with one or more substituents selected from halo,
CN, OH and NR7R8;

[0027] R7 and R8 are independently selected from: H,
(C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a;

[0030] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0031] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0032] In a second embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula A, wherein:

##STR00002##

is selected from:

##STR00003## ##STR00004## ##STR00005##

[0033] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0034] and all other substituents and variables are as defined in the
first embodiment;

[0035] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0036] In a third embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula B:

##STR00006##

wherein:

[0037] Ring Y is cyclobutyl, said cyclobutyl is substituted with Rx,
and further optionally substituted with one or more substituents selected
from: (C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, CO2H, halo, CN, OH and NR7R8,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8;

[0048] R7 and R8 are independently selected from: H,
(C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a;

[0049] Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl,
aryl, or heterocyclyl; and

[0051] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0052] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0053] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0054] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0055] In a fifth embodiment the inhibitors of the instant invention are
illustrated by the Formula D:

[0061] R7 and R8 are independently selected from: H,
(C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C9)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a;

[0062] Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl,
aryl, or heterocyclyl; and

[0064] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0065] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0066] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0067] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0068] In a sixth embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula E:

[0074] R7 and R8 are independently selected from: H,
(C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-aryl, (C═O)aOb-heterocyclyl,
(C2-C10)alkenyl, (C2-C10)alkynyl, SH,
SO2Ra, and (C═O)aNRb2, said alkyl,
cycloalkyl, aryl, heterocyclyl, alkenyl, and alkynyl is optionally
substituted with one or more substituents selected from R6a, or
R7 and R8 can be taken together with the nitrogen to which they
are attached to form a monocyclic or bicyclic heterocycle with 3-7
members in each ring and optionally containing, in addition to the
nitrogen, one or two additional heteroatoms selected from N, O and S,
said monocyclic or bicyclic heterocycle optionally substituted with one
or more substituents selected from R6a;

[0075] Ra is (C1-C6)alkyl, (C3-C6)cycloalkyl,
aryl, or heterocyclyl; and

[0077] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0078] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0079] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0080] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0081] In a seventh embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula C-1:

##STR00010##

wherein:

[0082] R1 is imidazolyl, triazolyl, or pyrimidyl, said imidazolyl,
triazolyl, and pyrimidyl is optionally substituted with one or more
(C1-C6)alkyl;

[0084] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0085] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0086] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0087] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0088] In an eighth embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula D-1:

##STR00011##

wherein:

[0089] R1 is pyridyl, said pyridyl is optionally substituted with one
or more (C1-C6)alkyl;

[0091] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0092] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0093] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0094] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0095] In a ninth embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula D-1:

##STR00012##

wherein:

[0096] R1 is (C1-C6)alkyl, NR7R8, phenyl,
pyridyl, pyrimidyl, pyrazinyl, azetidinyl, piperidinyl, or morpholinyl,
said alkyl, phenyl, pyridyl, pyrimidyl, pyrazinyl, azetidinyl,
piperidinyl, and morpholinyl is optionally substituted with one or more
substituents selected from: (C1-C6)alkyl, halo, OH, and
NR7R8, said alkyl is optionally substituted with one or more
substituents selected from: halo, and OH;

[0098] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0099] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0100] Bond: is a single or double bond, provided that when 10 is oxo,
then said bond is a single bond and adjacent N bears H;

[0101] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0102] In a tenth embodiment of this invention, the inhibitors of Akt
activity are illustrated by the Formula E-1:

##STR00013##

wherein:

[0103] R1 is pyrimidyl, said pyrimidyl is optionally substituted with
one or more (C1-C6)alkyl;

[0105] Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, OH and NR7R8, said alkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8;

[0106] Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, (C1-C6)alkoxy, halo, CN and OH,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; and

[0107] Bond: is a single or double bond, provided that when R1 is
oxo, then said bond is a single bond and adjacent N bears H;

[0108] or a pharmaceutically acceptable salt or a stereoisomer thereof.

[0201] The compounds of the present invention may have asymmetric centers,
chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.
Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,
1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as
individual diastereomers, with all possible isomers and mixtures thereof,
including optical isomers, all such stereoisomers being included in the
present invention.

[0202] In addition, the compounds disclosed herein may exist as tautomers
and both tautomeric forms are intended to be encompassed by the scope of
the invention, even though only one tautomeric structure is depicted. For
example the following is within the scope of the instant invention:

##STR00014## ##STR00015##

Tetrazoles exist as a mixture of 1H/2H tautomers. The tautomeric forms of
the tetrazol moiety are also within the scope of the instant invention.

[0203] This invention is also intended to encompass pro-drugs of the
compounds disclosed herein. A prodrug of any of the compounds can be made
using well known pharmacological techniques.

[0204] When any variable (e.g. R2, etc.) occurs more than one time in
any constituent, its definition on each occurrence is independent at
every other occurrence. Also, combinations of substituents and variables
are permissible only if such combinations result in stable compounds.
Lines drawn into the ring systems from substituents represent that the
indicated bond may be attached to any of the substitutable ring atoms. If
the ring system is bicyclic, it is intended that the bond be attached to
any of the suitable atoms on either ring of the bicyclic moiety.

[0205] It is understood that one or more silicon (Si) atoms can be
incorporated into the compounds of the instant invention in place of one
or more carbon atoms by one of ordinary skill in the art to provide
compounds that are chemically stable and that can be readily synthesized
by techniques known in the art from readily available starting materials.
Carbon and silicon differ in their covalent radius leading to differences
in bond distance and the steric arrangement when comparing analogous
C-element and Si-element bonds. These differences lead to subtle changes
in the size and shape of silicon-containing compounds when compared to
carbon. One of ordinary skill in the art would understand that size and
shape differences can lead to subtle or dramatic changes in potency,
solubility, lack of off target activity, packaging properties, and so on.
(Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G. A.
et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

[0206] It is understood that substituents and substitution patterns on the
compounds of the instant invention can be selected by one of ordinary
skill in the art to provide compounds that are chemically stable and that
can be readily synthesized by techniques known in the art, as well as
those methods set forth below, from readily available starting materials.
If a substituent is itself substituted with more than one group, it is
understood that these multiple groups may be on the same carbon or on
different carbons, so long as a stable structure results. The phrase
"optionally substituted with one or more substituents" should be taken to
be equivalent to the phrase "optionally substituted with at least one
substituent" and in such cases the preferred embodiment will have from
zero to four substituents, and the more preferred embodiment will have
from zero to three substituents.

[0207] As used herein, "alkyl" is intended to include both branched and
straight-chain saturated aliphatic hydrocarbon groups having the
specified number of carbon atoms. For example, C1-C10, as in
"(C1-C10)alkyl" is defined to include groups having 1, 2, 3, 4,
5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For
example, "(C1-C10)alkyl" specifically includes methyl, ethyl,
n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl,
octyl, nonyl, decyl, and so on.

[0208] The term "cycloalkyl" means a monocyclic saturated aliphatic
hydrocarbon group having the specified number of carbon atoms. For
example, "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl,
2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on.

[0209] "Alkoxy" represents either a cyclic or non-cyclic alkyl group of
indicated number of carbon atoms attached through an oxygen bridge.
"Alkoxy" therefore encompasses the definitions of alkyl and cycloalkyl
above.

[0210] If no number of carbon atoms is specified, the term "alkenyl"
refers to a non-aromatic hydrocarbon radical, straight, branched or
cyclic, containing from 2 to 10 carbon atoms and at least one carbon to
carbon double bond. Preferably one carbon to carbon double bond is
present, and up to four non-aromatic carbon-carbon double bonds may be
present. Thus, "(C2-C10)alkenyl" means an alkenyl radical
having from 2 to 10 carbon atoms. Alkenyl groups include ethenyl,
propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight,
branched or cyclic portion of the alkenyl group may contain double bonds
and may be substituted if a substituted alkenyl group is indicated.

[0211] The term "alkynyl" refers to a hydrocarbon radical straight,
branched or cyclic, containing from 2 to 10 carbon atoms and at least one
carbon to carbon triple bond. Up to three carbon-carbon triple bonds may
be present. Thus, "(C2-C10)alkynyl" means an alkynyl radical
having from 2 to 10 carbon atoms. Alkynyl groups include ethynyl,
propynyl, butynyl, 3-methylbutynyl and so on. The straight, branched or
cyclic portion of the alkynyl group may contain triple bonds and may be
substituted if a substituted alkynyl group is indicated.

[0212] In certain instances, substituents may be defined with a range of
carbons that includes zero, such as (C0-C6)alkylene-aryl. If
aryl is taken to be phenyl, this definition would include phenyl itself
as well as --CH2Ph, --CH2CH2Ph,
CH(CH3)CH2CH(CH3)Ph, and so on.

[0213] As used herein, "aryl" is intended to mean any stable monocyclic or
bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one
ring is aromatic. Examples of such aryl elements include phenyl,
naphthyl, tetrahydro-naphthyl, indanyl and biphenyl. In cases where the
aryl substituent is bicyclic and one ring is non-aromatic, it is
understood that attachment is via the aromatic ring.

[0214] The term heteroaryl, as used herein, represents a stable monocyclic
or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring
is aromatic and contains from 1 to 4 heteroatoms selected from the group
consisting of O, N and S. Heteroaryl groups within the scope of this
definition include but are not limited to: acridinyl, carbazolyl,
cinnolinyl, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furanyl,
thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl,
isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl,
pyrrolyl, tetrahydroquinoline. As with the definition of heterocycle
below, "heteroaryl" is also understood to include the N-oxide derivative
of any nitrogen-containing heteroaryl. In cases where the heteroaryl
substituent is bicyclic and one ring is non-aromatic or contains no
heteroatoms, it is understood that attachment is via the aromatic ring or
via the heteroatom containing ring, respectively. Such heteroaryl
moieties for substituent Q include but are not limited to:
2-benzimidazolyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl,
1-isoquinolinyl, 3-isoquinolinyl and 4-isoquinolinyl.

[0231] In another embodiment of Formula A, B, C, D and E, R1 is
selected from: oxo, (C═O)aOb(C1-C10)alkyl,
(C═O)aOb-aryl, (C═O)aNR7R8,
(C═O)aOb(C3-C8)cycloalkyl, and
(C═O)aOb-heterocyclyl, said alkyl, aryl, cycloalkyl, and
heterocyclyl is optionally substituted with one or more substituents
selected from R6; R6 is:
(C═O)aOb(C1-C10)alkyl,
(C═O)aObaryl, (C═O)aOb heterocyclyl, halo,
OH, Ob(C1-C6)perfluoroalkyl,
Oa(C═O)bNR7R8, oxo, or
(C═O)aOb(C3-C8)cycloalkyl; R7 and R8 in
the group of (C═O)aNR7R8, or
Oa(C═O)bNR7R8, are independently selected from:
H, and (C═O)aOb(C1-C10)alkyl; a is 0 or 1; and b
is 0 or 1.

[0232] In another embodiment of Formula A, B, C, D and E, R1 is
(C1-C6)alkyl, OH, (C═O)aNR7R8, phenyl,
imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, azetidinyl, piperidinyl, or morpholinyl, said alkyl, phenyl,
imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidyl, pyrazinyl,
pyridazinyl, azetidinyl, piperidinyl, and morpholinyl is optionally
substituted with one or more substituents selected from:
(C1-C6)alkyl, halo, OH, and (C═O)bNR7R8,
said alkyl is optionally substituted with one or more substituents
selected from: halo, and OH; R7 and R8 in the group of
(C═O)aNR7R8, or (C═O)bNR7R8, are
independently selected from: H, and (C1-C6)alkyl; a is 0 or 1;
and b is 0 or 1.

[0233] In another embodiment of Formula A, B, C, D and E, R1 is
imidazolyl, pyridyl, or pyrimidyl, said imidazolyl, triazolyl, pyridyl,
and pyrimidyl is optionally substituted with one or more
(C1-C6)alkyl.

[0234] In another embodiment of Formula A, B, C, D and E, R1 is
(C1-C6)alkyl, NR7R8, phenyl, pyridyl, pyrimidyl,
pyrazinyl, azetidinyl, piperidinyl, or morpholinyl, said alkyl, phenyl,
pyridyl, pyrimidyl, pyrazinyl, azetidinyl, piperidinyl, and morpholinyl
is optionally substituted with one or more substituents selected from:
(C1-C6)alkyl, halo, OH, and NR7R8, said alkyl is
optionally substituted with one or more substituents selected from: halo,
and OH; R7 and R8 are independently selected from: H, and
(C1-C6)alkyl.

[0235] In an embodiment of Formula A, B, C, D and E,
(C1-C6)alkyl for R1 is methyl or ethyl, which is
optionally substituted with OH.

[0236] In another embodiment of Formula A, B, C, D, D-1 and E,
(C1-C6)alkyl for R1 is methyl, ethyl, or propyl, which is
optionally substituted with one or more halo, preferably F.

[0237] In an embodiment of Formula A, B, C, D and E,
(C═O)aNR7R8 for 10 is (C═O)NH2.

[0238] In another embodiment of Formula A, B, C, D and E,
(C═O)aNR7R8 for R1 is NH2, or NHCH3.

[0239] In an embodiment of Formula D-1, NR7R8 for R1 is
NH2, or NHCH3.

[0240] In an embodiment of Formula A, B, C, D, E, C-1, D-1, and E-1,
(C1-C6)alkyl as the substituents for R1 is methyl or
ethyl, preferably methyl.

[0241] In an embodiment of Formula A, B, C, D and E, halo as the
substituents for R1 is F.

[0242] In an embodiment of Formula A, B, C, D and E, R7 and R8
in the formula:

##STR00023##

are independently selected from: H,
(C═O)aOb(C1-C10)alkyl,
(C═O)aOb(C3-C8)cycloalkyl,
(C═O)aOb-heterocyclyl, SO2Ra, and
(C═O)aNRb2, said alkyl, cycloalkyl, aryl, and
heterocyclyl is optionally substituted with one or more substituents
selected from R6a; R6a is selected from:
(C═O)aOb(C1-C10)alkyl, OH, halo, CN,
(C0-C6)alkylene-aryl, and
(C0-C6)alkylene-heterocyclyl, said alkyl, aryl, and
heterocyclyl is optionally substituted with up to three substituents
selected from Rb, halogen, and oxo; Ra is
(C1-C6)alkyl, aryl, or heterocyclyl, said alkyl, aryl, and
heterocyclyl is optionally substituted with one or more substituents
selected from Rc; Rb is independently: H,
(C1-C6)alkyl, aryl, or heterocyclyl, said alkyl, aryl, and
heterocyclyl is optionally substituted with one or more aryl; Rc is
independently: aryl, halo, or CN, said aryl is optionally substituted
with one or more CN; a is 0 or 1; and b is 0 or 1.

[0243] In another embodiment of Formula A, B, C, D and E, both R7 and
R8 in the formula:

##STR00024##

are H.

[0244] In an embodiment of Formula A, Ring Y is cyclobutyl, said
cyclobutyl is substituted with Rx, and further optionally
substituted with one or more substituents selected from:
(C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, CO2H, halo, CN, OH and NR7R8,
said alkyl, cycloalkyl, and alkoxy is optionally substituted with one or
more substituents selected from halo, CN, OH and NR7R8; Rx
is selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halo,
OH and NR7R8, said alkyl, and alkoxy is optionally substituted
with one or more substituents selected from halo, CN, OH and
NR7R8; and R7 and R8 in the group of NR7R8
as Rx or the substituents, are independently selected from: H, and
(C1-C6)alkyl.

[0245] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with Rx, and further optionally
substituted with one or more substituents selected from:
(C1-C6)alkyl, (C3-C6)cycloalkyl,
(C1-C6)alkoxy, halo, CN and OH, said alkyl, cycloalkyl, and
alkoxy is optionally substituted with one or more substituents selected
from halo, CN, OH and NR7R8; Rx is selected from:
(C1-C6)alkyl, (C1-C6)alkoxy, halo, OH and
NR7R8, said alkyl, and alkoxy is optionally substituted with
one or more substituents selected from halo, CN, OH and NR7R8;
and R7 and R8 in the group of NR7R8 as Rx or the
substituents, are independently selected from: H, and
(C1-C6)alkyl.

[0246] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with Rx; and further optionally
substituted with one or more substituents selected from:
(C1-C6)alkyl, (C3-C6)cycloalkyl, and halo, said
alkyl, and cycloalkyl is optionally substituted with one or more
substituents selected from halo, CN, OH and NR7R8; Rx is
selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halo, or
OH, said alkyl, and alkoxy is optionally substituted with one or more
substituents selected from halo, CN, OH and NR7R8; and R7
and R8 in the group of NR7R8 as the substituents, are
independently selected from: H, and (C1-C6)alkyl.

[0247] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with Rx; and further optionally
substituted with one or more substituents selected from:
(C1-C6)alkyl, (C3-C6)cycloalkyl, and halo, said
alkyl, and cycloalkyl is optionally substituted with one or more
substituents selected from halo, and OH; Rx is selected from:
(C1-C6)alkyl, (C1-C6)alkoxy, halo, or OH, said alkyl,
and alkoxy is optionally substituted with one or more substituents
selected from halo, and OH.

[0248] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with OH, and further optionally
substituted with one substituent selected from: (C1-C6)alkyl,
and (C3-C6)cycloalkyl, said alkyl, and cycloalkyl is optionally
substituted with OH.

[0249] In yet another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with OH, and further optionally
substituted with one substituent selected from: methyl and cyclopropyl,
said methyl is optionally substituted with OH.

[0250] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with halo, preferably F, and further
optionally substituted with one substituent selected from:
(C1-C6)alkyl, and halo, said alkyl is optionally substituted
with one or more substituents selected from halo, and OH.

[0251] In yet another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with halo, preferably F, and further
optionally substituted with one substituent selected from: methyl, and F.

[0252] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with (C1-C6)alkyl, preferably
methyl.

[0253] In another embodiment of Formula A and B, Ring Y is cyclobutyl,
said cyclobutyl is substituted with (C1-C6)alkoxy, preferably
methoxy.

[0254] In an embodiment of Formula C, D, E, C-1, D-1, and E-1, Rx is
selected from: (C1-C6)alkyl, (C1-C6)alkoxy, halo, and
OH, said alkyl, and alkoxy is optionally substituted with one or more
substituents selected from halo, CN, OH and NR7R8; Ry is
selected from: H, (C1-C6)alkyl, (C3-C6)cycloalkyl,
and halo, said alkyl, cycloalkyl, and alkoxy is optionally substituted
with one or more substituents selected from halo, CN, OH and
NR7R8; and R7 and R8 in the group of NR7R8
as the substituents, are independently selected from: H, and
(C1-C6)alkyl.

[0255] In another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is selected from: (C1-C6)alkyl,
(C1-C6)alkoxy, halo, and OH, said alkyl, and alkoxy is
optionally substituted with one or more substituents selected from halo,
and OH; Ry is selected from: H, (C1-C6)alkyl,
(C3-C6)cycloalkyl, and halo, said alkyl, cycloalkyl, and alkoxy
is optionally substituted with one or more substituents selected from
halo, and OH.

[0258] In another embodiment of Formula A, B, C, D, E, C-1, D-1, and E-1,
halo for Rx is F.

[0259] In another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is OH; and Ry is selected from: H, (C1-C6)alkyl,
and (C3-C6)cycloalkyl, said alkyl and cycloalkyl are optionally
substituted with OH.

[0260] In yet another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is OH; and Ry is selected from: H, methyl, and cyclopropyl,
said methyl is optionally substituted with OH.

[0261] In another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is halo, preferably F; and Ry is selected from: H,
(C1-C6)alkyl, and halo, said alkyl is optionally substituted
with one or more substituents selected from halo, and OH.

[0263] In another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is (C1-C6)alkyl, preferably methyl; and Ry is H.

[0264] In another embodiment of Formula C, D, E, C-1, D-1, and E-1,
Rx is (C1-C6)alkoxy, preferably methoxy; and Ry is H.

[0265] Included in the instant invention is the free form of compounds of
Formula A, as well as the pharmaceutically acceptable salts and
stereoisomers thereof. Some of the isolated specific compounds
exemplified herein are the protonated salts of amine compounds. The term
"free form" refers to the amine compounds in non-salt form. The
encompassed pharmaceutically acceptable salts not only include the
isolated salts exemplified for the specific compounds described herein,
but also all the typical pharmaceutically acceptable salts of the free
form of compounds of Formula A. The free farm of the specific salt
compounds described may be isolated using techniques known in the art.
For example, the free form may be regenerated by treating the salt with a
suitable dilute aqueous base solution such as dilute aqueous NaOH,
potassium carbonate, ammonia and sodium bicarbonate. The free forms may
differ from their respective salt forms somewhat in certain physical
properties, such as solubility in polar solvents, but the acid and base
salts are otherwise pharmaceutically equivalent to their respective free
forms for purposes of the invention.

[0266] The pharmaceutically acceptable salts of the instant compounds can
be synthesized from the compounds of this invention which contain a basic
or acidic moiety by conventional chemical methods. Generally, the salts
of the basic compounds are prepared either by ion exchange chromatography
or by reacting the free base with stoichiometric amounts or with an
excess of the desired salt-forming inorganic or organic acid in a
suitable solvent or various combinations of solvents. Similarly, the
salts of the acidic compounds are formed by reactions with the
appropriate inorganic or organic base.

[0267] Thus, pharmaceutically acceptable salts of the compounds of this
invention include the conventional non-toxic salts of the compounds of
this invention as formed by reacting a basic instant compound with an
inorganic or organic acid. For example, conventional non-toxic salts
include those derived from inorganic acids such as hydrochloric,
hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well
as salts prepared from organic acids such as acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic,
maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic,
sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane disulfonic, oxalic, isethionic, trifluoroacetic (TFA) and the
like.

[0269] The preparation of the pharmaceutically acceptable salts described
above and other typical pharmaceutically acceptable salts is more fully
described by Berg et al., "Pharmaceutical Salts," J. Pharm. Sci.,
1977:66:1-19.

[0270] It will also be noted that the compounds of the present invention
are potentially internal salts or zwitterions, since under physiological
conditions a deprotonated acidic moiety in the compound, such as a
carboxyl group, may be anionic, and this electronic charge might then be
balanced off internally against the cationic charge of a protonated or
alkylated basic moiety, such as a quaternary nitrogen atom.

UTILITY

[0271] The compounds of the instant invention are inhibitors of the
activity of Akt and are thus useful in the treatment of cancer, in
particular cancers associated with irregularities in the activity of Akt
and downstream cellular targets of Akt. Such cancers include, but are not
limited to, ovarian, pancreatic, breast and prostate cancer, as well as
cancers (including glioblastoma) where the tumor suppressor PTEN is
mutated (Cheng et al., Proc. Natl. Acad. Sci. (1992) 89:9267-9271; Cheng
et al., Proc. Natl. Acad. Sci. (1996) 93:3636-3641; Bellacosa et al.,
Int. J. Cancer (1995) 64:280-285; Nakatani et al., J. Biol. Chem. (1999)
274:21528-21532; Graff, Expert. Opin. Ther. Targets (2002) 6(1):103-113;
and Yamada and Araki, J. Cell Science. (2001) 114:2375-2382; Mischel and
Cloughesy, Brain Pathol. (2003) 13(1):52-61). Cancers where Akt itself is
activated by gene amplification or mutations may also be treated by the
compounds. Human breast, colorectal and ovarian cancers where a somatic
mutation in a pleckstrin homology domain (PH) of AKT1 (E17K mutant; the
glutamic acid (E) at position 17 of the amino acid sequence of the PH
domain of AKT1 is replaced by a lysine (K)) is reported (Carpten et al,
Nature 448: 439-444 (2007)).

[0273] Cancers that may be treated by the compounds, compositions and
methods of the invention include, but are not limited to: breast,
prostate, colon, colorectal, lung, non-small cell lung, brain,
testicular, stomach, pancreas, skin, small intestine, large intestine,
throat, head and neck, oral, bone, liver, bladder, kidney, thyroid and
blood.

[0274] Cancers that may be treated by the compounds, compositions and
methods of the invention include: breast, prostate, colon, ovarian,
colorectal, lung and non-small cell lung.

[0275] Cancers that may be treated by the compounds, compositions and
methods of the invention include: breast, colon, (colorectal) and lung
(non-small cell lung).

[0276] Cancers that may be treated by the compounds, compositions and
methods of the invention include: lymphoma and leukemia.

[0277] The compounds of the instant invention are useful for the treatment
of breast cancer.

[0278] The compounds of the instant invention are useful for the treatment
of prostate cancer.

[0280] Tumors which have undergone neovascularization show an increased
potential for metastasis. In fact, angiogenesis is essential for tumor
growth and metastasis. (S. P. Cunningham, et al., Can. Research, 61:
3206-3211 (2001)). The Akt inhibitors disclosed in the present
application are therefore also useful to prevent or decrease tumor cell
metastasis.

[0281] Further included within the scope of the invention is a method of
treating or preventing a disease in which angiogenesis is implicated,
which is comprised of administering to a mammal in need of such treatment
a therapeutically effective amount of a compound of the present
invention. Ocular neovascular diseases are an example of conditions where
much of the resulting tissue damage can be attributed to aberrant
infiltration of blood vessels in the eye (see WO 00/30651, published 2
Jun. 2000). The undesirable infiltration can be triggered by ischemic
retinopathy, such as that resulting from diabetic retinopathy,
retinopathy of prematurity, retinal vein occlusions, etc., or by
degenerative diseases, such as the choroidal neovascularization observed
in age-related macular degeneration. Inhibiting the growth of blood
vessels by administration of the present compounds would therefore
prevent the infiltration of blood vessels and prevent or treat diseases
where angiogenesis is implicated, such as ocular diseases like retinal
vascularization, diabetic retinopathy, age-related macular degeneration,
and the like.

[0282] Further included within the scope of the invention is a method of
treating or preventing a non-malignant disease in which angiogenesis is
implicated, including but not limited to: ocular diseases (such as,
retinal vascularization, diabetic retinopathy and age-related macular
degeneration), atherosclerosis, arthritis, psoriasis, obesity and
Alzheimer's disease (Dredge et al., Expert Opin. Biol. Ther. (2002)
2(8):953-966). In another embodiment, a method of treating or preventing
a disease in which angiogenesis is implicated includes: ocular diseases
(such as, retinal vascularization, diabetic retinopathy and age-related
macular degeneration), atherosclerosis, arthritis and psoriasis.

[0283] Further included within the scope of the invention is a method of
treating hyperproliferative disorders such as restenosis, inflammation,
autoimmune diseases and allergy/asthma.

[0284] Further included within the scope of the instant invention is the
use of the instant compounds to coat stents and therefore the use of the
instant compounds on coated stents for the treatment and/or prevention of
restenosis (WO03/032809).

[0285] Further included within the scope of the instant invention is the
use of the instant compounds for the treatment and/or prevention of
osteoarthritis (WO03/035048).

[0286] Further included within the scope of the invention is a method of
treating hyperinsulinism.

[0287] The compounds of the invention are also useful in preparing a
medicament that is useful in treating the diseases described above, in
particular cancer.

[0288] In an embodiment of the invention, the instant compound is a
selective inhibitor whose inhibitory efficacy is dependent on the PH
domain. In this embodiment, the compound exhibits a decrease in in vitro
inhibitory activity or no in vitro inhibitory activity against truncated
Akt proteins lacking the PH domain.

[0289] In a further embodiment, the instant compound is selected from the
group of a selective inhibitor of Akt1, a selective inhibitor of Akt2 and
a selective inhibitor of both Akt1 and Akt2, preferably a selective
inhibitor of Akt1.

[0290] In another embodiment, the instant compound is selected from the
group of a selective inhibitor of Akt1, a selective inhibitor of Akt2, a
selective inhibitor of Akt3 and a selective inhibitor of two of the three
Akt isoforms.

[0291] In another embodiment, the instant compound is a selective
inhibitor of all three Akt isoforms, but is not an inhibitor of one, two
or all of such Akt isoforms that have been modified to delete the PH
domain, the hinge region or both the PH domain and the hinge region.

[0292] The present invention is further directed to a method of inhibiting
Akt activity, preferably Akt1 activity, which comprises administering to
a mammal in need thereof a pharmaceutically effective amount of the
instant compound.

[0293] The compounds of this invention may be administered to mammals,
including humans, either alone or, in combination with pharmaceutically
acceptable carriers, excipients or diluents, in a pharmaceutical
composition, according to standard pharmaceutical practice. The compounds
can be administered orally or parenterally, including the intravenous,
intramuscular, intraperitoneal, subcutaneous, rectal and topical routes
of administration.

[0294] The pharmaceutical compositions containing the active ingredient
may be in a form suitable for oral use, for example, as tablets, troches,
lozenges, aqueous or oily suspensions, dispersible powders or granules,
emulsions, hard or soft capsules, or syrups or elixirs. Compositions
intended for oral use may be prepared according to any method known to
the art for the manufacture of pharmaceutical compositions and such
compositions may contain one or more agents selected from the group
consisting of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients which are
suitable for the manufacture of tablets. These excipients may be for
example, inert diluents, such as calcium carbonate, sodium carbonate,
lactose, calcium phosphate or sodium phosphate; granulating and
disintegrating agents, for example, microcrystalline cellulose, sodium
crosscarmellose, corn starch, or alginic acid; binding agents, for
example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricating
agents, for example, magnesium stearate, stearic acid or talc. The
tablets may be uncoated or they may be coated by known techniques to mask
the unpleasant taste of the drug or delay disintegration and absorption
in the gastrointestinal tract and thereby provide a sustained action over
a longer period. For example, a water soluble taste masking material such
as hydroxypropylmethyl-cellulose or hydroxypropylcellulose, or a time
delay material such as ethyl cellulose, cellulose acetate buryrate may be
employed.

[0295] Formulations for oral use may also be presented as hard gelatin
capsules wherein the active ingredient is mixed with an inert solid
diluent, for example, calcium carbonate, calcium phosphate or kaolin, or
as soft gelatin capsules wherein the active ingredient is mixed with
water soluble carrier such as polyethylene glycol or an oil medium, for
example peanut oil, liquid paraffin, or olive oil.

[0296] Aqueous suspensions contain the active material in admixture with
excipients suitable for the manufacture of aqueous suspensions. Such
excipients are suspending agents, for example sodium
carboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,
sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;
dispersing or wetting agents may be a naturally-occurring phosphatide,
for example lecithin, or condensation products of an alkylene oxide with
fatty acids, for example polyoxyethylene stearate, or condensation
products of ethylene oxide with long chain aliphatic alcohols, for
example heptadecaethylene-oxycetanol, or condensation products of
ethylene oxide with partial esters derived from fatty acids and a hexitol
such as polyoxyethylene sorbitol monooleate, or condensation products of
ethylene oxide with partial esters derived from fatty acids and hexitol
anhydrides, for example polyethylene sorbitan monooleate. The aqueous
suspensions may also contain one or more preservatives, for example
ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or
more flavoring agents, and one or more sweetening agents, such as
sucrose, saccharin or aspartame.

[0297] Oily suspensions may be formulated by suspending the active
ingredient in a vegetable oil, for example arachis oil, olive oil, sesame
oil or coconut oil, or in mineral oil such as liquid paraffin. The oily
suspensions may contain a thickening agent, for example beeswax, hard
paraffin or cetyl alcohol. Sweetening agents such as those set forth
above, and flavoring agents may be added to provide a palatable oral
preparation. These compositions may be preserved by the addition of an
anti-oxidant such as butylated hydroxyanisol or alpha-tocopherol.

[0298] Dispersible powders and granules suitable for preparation of an
aqueous suspension by the addition of water provide the active ingredient
in admixture with a dispersing or wetting agent, suspending agent and one
or more preservatives. Suitable dispersing or wetting agents and
suspending agents are exemplified by those already mentioned above.
Additional excipients, for example sweetening, flavoring and coloring
agents, may also be present. These compositions may be preserved by the
addition of an anti-oxidant such as ascorbic acid.

[0299] The pharmaceutical compositions of the invention may also be in the
form of an oil-in-water emulsion. The oily phase may be a vegetable oil,
for example olive oil or arachis oil, or a mineral oil, for example
liquid paraffin or mixtures of these. Suitable emulsifying agents may be
naturally-occurring phosphatides, for example soy bean lecithin, and
esters or partial esters derived from fatty acids and hexitol anhydrides,
for example sorbitan monooleate, and condensation products of the said
partial esters with ethylene oxide, for example polyoxyethylene sorbitan
monooleate. The emulsions may also contain sweetening, flavouring agents,
preservatives and antioxidants.

[0300] Syrups and elixirs may be formulated with sweetening agents, for
example glycerol, propylene glycol, sorbitol or sucrose. Such
formulations may also contain a demulcent, a preservative, flavoring and
coloring agents and antioxidant.

[0301] The pharmaceutical compositions may be in the form of sterile
injectable aqueous solutions. Among the acceptable vehicles and solvents
that may be employed are water, Ringer's solution and isotonic sodium
chloride solution.

[0302] The sterile injectable preparation may also be a sterile injectable
oil-in-water microemulsion where the active ingredient is dissolved in
the oily phase. For example, the active ingredient may be first dissolved
in a mixture of soybean oil and lecithin. The oil solution then
introduced into a water and glycerol mixture and processed to form a
microemulation.

[0303] The injectable solutions or microemulsions may be introduced into a
patient's blood-stream by local bolus injection. Alternatively, it may be
advantageous to administer the solution or microemulsion in such a way as
to maintain a constant circulating concentration of the instant compound.
In order to maintain such a constant concentration, a continuous
intravenous delivery device may be utilized. An example of such a device
is the Deltec CADD-PLUS® model 5400 intravenous pump.

[0304] The pharmaceutical compositions may be in the form of a sterile
injectable aqueous or oleagenous suspension for intramuscular and
subcutaneous administration. This suspension may be formulated according
to the known art using those suitable dispersing or wetting agents and
suspending agents which have been mentioned above. The sterile injectable
preparation may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example as a
solution in 1,3-butane diol. In addition, sterile, fixed oils are
conventionally employed as a solvent or suspending medium. For this
purpose any bland fixed oil may be employed including synthetic mono- or
diglycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.

[0305] Compounds of the present invention may also be administered in the
fowl of suppositories for rectal administration of the drug. These
compositions can be prepared by mixing the drug with a suitable
non-irritating excipient which is solid at ordinary temperatures but
liquid at the rectal temperature and will therefore melt in the rectum to
release the drug. Such materials include cocoa butter, glycerinated
gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of
various molecular weights and fatty acid esters of polyethylene glycol.

[0306] For topical use, creams, ointments, jellies, solutions or
suspensions, etc., containing the compound of the present invention are
employed. (For purposes of this application, topical application shall
include mouth washes and gargles.)

[0307] The compounds for the present invention can be administered in
intranasal form via topical use of suitable intranasal vehicles and
delivery devices, or via transdermal routes, using those forms of
transdermal skin patches well known to those of ordinary skill in the
art. To be administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen. Compounds of the present
invention may also be delivered as a suppository employing bases such as
cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures
of polyethylene glycols of various molecular weights and fatty acid
esters of polyethylene glycol.

[0308] When a composition according to this invention is administered into
a human subject, the daily dosage will normally be determined by the
prescribing physician with the dosage generally varying according to the
age, weight, and response of the individual patient, as well as the
severity of the patient's symptoms.

[0309] The dosage regimen utilizing the compounds of the instant invention
can be selected in accordance with a variety of factors including type,
species, age, weight, sex and the type of cancer being treated; the
severity (i.e., stage) of the cancer to be treated; the route of
administration; the renal and hepatic function of the patient; and the
particular compound or salt thereof employed. An ordinarily skilled
physician or veterinarian can readily determine and prescribe the
effective amount of the drug required to treat, for example, to prevent,
inhibit (fully or partially) or arrest the progress of the disease. For
example, compounds of the instant invention can be administered in a
total daily dose of up to 10,000 mg. Compounds of the instant invention
can be administered once daily (QD), or divided into multiple daily doses
such as twice daily (BID), and three times daily (TID). Compounds of the
instant invention can be administered at a total daily dosage of up to
10,000 mg, e.g., 2,000 mg, 3,000 mg, 4,000 mg, 6,000 mg, 8,000 mg or
10,000 mg, which can be administered in one daily dose or can be divided
into multiple daily doses as described above.

[0310] For example, compounds of the instant invention can be administered
in a total daily dose of up to 1,000 mg. Compounds of the instant
invention can be administered once daily (QD), or divided into multiple
daily doses such as twice daily (BID), and three times daily (TID).
Compounds of the instant invention can be administered at a total daily
dosage of up to 1,000 mg, e.g., 200 mg, 300 mg, 400 mg, 600 mg, 800 mg or
1,000 mg, which can be administered in one daily dose or can be divided
into multiple daily doses as described above.

[0311] In addition, the administration can be continuous, i.e., every day,
or intermittently. The terms "intermittent" or "intermittently" as used
herein means stopping and starting at either regular or irregular
intervals. For example, intermittent administration of a compound of the
instant invention may be administration one to six days per week or it
may mean administration in cycles (e.g. daily administration for two to
eight consecutive weeks, then a rest period with no administration for up
to one week) or it may mean administration on alternate days.

[0312] In addition, the compounds of the instant invention may be
administered according to any of the schedules described above,
consecutively for a few weeks, followed by a rest period. For example,
the compounds of the instant invention may be administered according to
any one of the schedules described above from two to eight weeks,
followed by a rest period of one week, or twice daily at a dose of
100-500 mg for three to five days a week. In another particular
embodiment, the compounds of the instant invention may be administered
three times daily for two consecutive weeks, followed by one week of
rest.

[0313] Any one or more of the specific dosages and dosage schedules of the
compounds of the instant invention, may also be applicable to any one or
more of the therapeutic agents to be used in the combination treatment
(hereinafter referred to as the "second therapeutic agent").

[0314] Moreover, the specific dosage and dosage schedule of this second
therapeutic agent can further vary, and the optimal dose, dosing schedule
and route of administration will be determined based upon the specific
second therapeutic agent that is being used.

[0315] Of course, the route of administration of the compounds of the
instant invention is independent of the route of administration of the
second therapeutic agent. In an embodiment, the administration for a
compound of the instant invention is oral administration. In another
embodiment, the administration for a compound of the instant invention is
intravenous administration. Thus, in accordance with these embodiments, a
compound of the instant invention is administered orally or
intravenously, and the second therapeutic agent can be administered
orally, parenterally, intraperitoneally, intravenously, intraarterially,
transdermally, sublingually, intramuscularly, rectally, transbuccally,
intranasally, liposomally, via inhalation, vaginally, intraocularly, via
local delivery by catheter or stent, subcutaneously, intraadiposally,
intraarticularly, intrathecally, or in a slow release dosage form.

[0316] In addition, a compound of the instant invention and second
therapeutic agent may be administered by the same mode of administration,
i.e. both agents administered e.g. orally, by IV. However, it is also
within the scope of the present invention to administer a compound of the
instant invention by one mode of administration, e.g. oral, and to
administer the second therapeutic agent by another mode of
administration, e.g. IV or any other ones of the administration modes
described hereinabove.

[0317] The first treatment procedure, administration of a compound of the
instant invention, can take place prior to the second treatment
procedure, i.e., the second therapeutic agent, after the treatment with
the second therapeutic agent, at the same time as the treatment with the
second therapeutic agent, or a combination thereof. For example, a total
treatment period can be decided for a compound of the instant invention.
The second therapeutic agent can be administered prior to onset of
treatment with a compound of the instant invention or following treatment
with a compound of the instant invention. In addition, anti-cancer
treatment can be administered during the period of administration of a
compound of the instant invention but does not need to occur over the
entire treatment period of a compound of the instant invention.

[0318] The instant compounds are also useful in combination with
therapeutic, chemotherapeutic and anti-cancer agents. Combinations of the
presently disclosed compounds with therapeutic, chemotherapeutic and
anti-cancer agents are within the scope of the invention. Examples of
such agents can be found in Cancer Principles and Practice of Oncology by
V. T. Devita and S. Hellman (editors), 6th edition (Feb. 15, 2001),
Lippincott Williams & Wilkins Publishers. A person of ordinary skill in
the art would be able to discern which combinations of agents would be
useful based on the particular characteristics of the drugs and the
cancer involved. Such agents include the following: estrogen receptor
modulators, androgen receptor modulators, retinoid receptor modulators,
cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein
transferase inhibitors, HMG-CoA reductase inhibitors and other
angiogenesis inhibitors, HIV protease inhibitors, reverse transcriptase
inhibitors, inhibitors of cell proliferation and survival signaling,
bisphosphonates, aromatase inhibitors, siRNA therapeutics,
γ-secretase inhibitors, agents that interfere with receptor
tyrosine kinases (RTKs) and agents that interfere with cell cycle
checkpoints. The instant compounds are particularly useful when
co-administered with radiation therapy.

[0319] "Estrogen receptor modulators" refers to compounds that interfere
with or inhibit the binding of estrogen to the receptor, regardless of
mechanism. Examples of estrogen receptor modulators include, but are not
limited to, tamoxifen, raloxifene, idoxifene, LY353381, LY117081,
toremifene, fulvestrant,
4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]ph-
enyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,
4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

[0320] "Androgen receptor modulators" refers to compounds which interfere
or inhibit the binding of androgens to the receptor, regardless of
mechanism. Examples of androgen receptor modulators include finasteride
and other 5α-reductase inhibitors, nilutamide, flutamide,
bicalutamide, liarozole, and abiraterone acetate.

[0328] Examples of inhibitors of mitotic kinesins, and in particular the
human mitotic kinesin KSP, are described in Publications WO03/039460,
WO03/050064, WO03/050122, WO03/049527, WO03/049679, WO03/049678,
WO04/039774, WO03/079973, WO03/099211, WO03/105855, WO03/106417,
WO04/037171, WO04/058148, WO04/058700, WO04/126699, WO05/018638,
WO05/019206, WO05/019205, WO05/018547, WO05/017190, US200510176776. In an
embodiment inhibitors of mitotic kinesins include, but are not limited to
inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E, inhibitors
of MCAK and inhibitors of Rab6-KIFL.

[0329] Examples of "histone deacetylase inhibitors" include, but are not
limited to, SAHA, TSA, oxamflatin, PXD101, MG98 and scriptaid. Further
reference to other histone deacetylase inhibitors may be found in the
following manuscript; Miller, T. A. et al. J. Med. Chem. 46(24):5097-5116
(2003).

[0330] "Inhibitors of kinases involved in mitotic progression" include,
but are not limited to, inhibitors of aurora kinase, inhibitors of
Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of
bub-1 and inhibitors of bub-R1. An example of an "aurora kinase
inhibitor" is VX-680.

[0332] Examples of monoclonal antibody targeted therapeutic agents include
those therapeutic agents which have cytotoxic agents or radioisotopes
attached to a cancer cell specific or target cell specific monoclonal
antibody. Examples include Bexxar.

[0333] "HMG-CoA reductase inhibitors" refers to inhibitors of
3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase
inhibitors that may be used include but are not limited to lovastatin
(MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039),
simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and
4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227,
4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®;
see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853,
5,290,946 and 5,356,896), atorvastatin (LIPITOR®; see U.S. Pat. Nos.
5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (also
known as rivastatin and BAYCHOL®; see U.S. Pat. No. 5,177,080). The
structural formulas of these and additional HMG-CoA reductase inhibitors
that may be used in the instant methods are described at page 87 of M.
Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5
Feb. 1996) and U.S. Pat. Nos. 4,782,084 and 4,885,314. The term HMG-CoA
reductase inhibitor as used herein includes all pharmaceutically
acceptable lactone and open-acid forms (i.e., where the lactone ring is
opened to form the free acid) as well as salt and ester forms of
compounds which have HMG-CoA reductase inhibitory activity, and therefor
the use of such salts, esters, open-acid and lactone forms is included
within the scope of this invention.

[0334] "Prenyl-protein transferase inhibitor" refers to a compound which
inhibits any one or any combination of the prenyl-protein transferase
enzymes, including farnesyl-protein transferase (FPTase),
geranylgeranyl-protein transferase type I (GGPTase-I), and
geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab
GGPTase).

[0337] Other therapeutic agents that modulate or inhibit angiogenesis and
may also be used in combination with the compounds of the instant
invention include agents that modulate or inhibit the coagulation and
fibrinolysis systems (see review in Clin. Chem. La. Med. 38:679-692
(2000)). Examples of such agents that modulate or inhibit the coagulation
and fibrinolysis pathways include, but are not limited to, heparin (see
Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and
carboxypeptidase U inhibitors (also known as inhibitors of active
thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res.
101:329-354 (2001)). TAM inhibitors have been described in U.S. Ser. Nos.
60/310,927 (filed Aug. 8, 2001) and 60/349,925 (filed Jan. 18, 2002).

[0338] "Agents that interfere with cell cycle checkpoints" refer to
compounds that inhibit protein kinases that transduce cell cycle
checkpoint signals, thereby sensitizing the cancer cell to DNA damaging
agents. Such agents include inhibitors of ATR, ATM, the CHK11 and CHK12
kinases and cdk and cdc kinase inhibitors and are specifically
exemplified by 7-hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and
BMS-387032.

[0339] "Agents that interfere with receptor tyrosine kinases (RTKs)" refer
to compounds that inhibit RTKs and therefore mechanisms involved in
oncogenesis and tumor progression. Such agents include inhibitors of
c-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors of
RTKs as described by Bume-Jensen and Hunter, Nature, 411:355-365, 2001.

[0341] As described above, the combinations with NSAID's are directed to
the use of NSAID's which are potent COX-2 inhibiting agents. For purposes
of this specification an NSAID is potent if it possesses an IC50 for
the inhibition of COX-2 of 1 μM or less as measured by cell or
microsomal assays.

[0342] The invention also encompasses combinations with NSAID's which are
selective COX-2 inhibitors. For purposes of this specification NSAID's
which are selective inhibitors of COX-2 are defined as those which
possess a specificity for inhibiting COX-2 over COX-1 of at least 100
fold as measured by the ratio of IC50 for COX-2 over IC50 for
COX-1 evaluated by cell or microsomal assays. Such compounds include, but
are not limited to those disclosed in U.S. Pat. No. 5,474,995, U.S. Pat.
No. 5,861,419, U.S. Pat. No. 6,001,843, U.S. Pat. No. 6,020,343, U.S.
Pat. No. 5,409,944, U.S. Pat. No. 5,436,265, U.S. Pat. No. 5,536,752,
U.S. Pat. No. 5,550,142, U.S. Pat. No. 5,604,260, U.S. Pat. No.
5,698,584, U.S. Pat. No. 5,710,140, WO 94/15932, U.S. Pat. No. 5,344,991,
U.S. Pat. No. 5,134,142, U.S. Pat. No. 5,380,738, U.S. Pat. No.
5,393,790, U.S. Pat. No. 5,466,823, U.S. Pat. No. 5,633,272 and U.S. Pat.
No. 5,932,598, all of which are hereby incorporated by reference.

[0343] Inhibitors of COX-2 that are particularly useful in the instant
method of treatment are:
3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or
a pharmaceutically acceptable salt thereof.

[0344] Compounds that have been described as specific inhibitors of COX-2
and are therefore useful in the present invention include, but are not
limited to, the following: parecoxib, BEXTRA® and CELEBREX® or a
pharmaceutically acceptable salt thereof.

[0346] As used above, "integrin blockers" refers to compounds which
selectively antagonize, inhibit or counteract binding of a physiological
ligand to the αvβ3 integrin, to compounds which
selectively antagonize, inhibit or counteract binding of a physiological
ligand to the αvβ5 integrin, to compounds which antagonize,
inhibit or counteract binding of a physiological ligand to both the
αvβ3 integrin and the αvβ5
integrin, and to compounds which antagonize, inhibit or counteract the
activity of the particular integrin(s) expressed on capillary endothelial
cells. The term also refers to antagonists of the
αvβ6, αvβ8,
α5β1, α6β1 and
α6β4 integrins. The term also refers to antagonists
of any combination of αvβ3,
αvβ5, αvβ6,
αvβ8, α1β1,
α2β1, α5β1,
α6β1 and α6β4 integrins.

[0348] Combinations with compounds other than anti-cancer compounds are
also encompassed in the instant methods. For example, combinations of the
instantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists
and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment
of certain malignancies. PPAR-γ and PPAR-δ are the nuclear
peroxisome proliferator-activated receptors γ and δ. The
expression of PPAR-γ on endothelial cells and its involvement in
angiogenesis has been reported in the literature (see J. Cardiovasc.
Pharmacol. 1998; 31:909-913; J. Biol. Chem. 1999; 274:9116-9121; Invest.
Ophthalmol. Vis. Sci. 2000; 41:2309-2317). More recently, PPAR-γ
agonists have been shown to inhibit the angiogenic response to VEGF in
vitro; both troglitazone and rosiglitazone maleate inhibit the
development of retinal neovascularization in mice. (Arch. Ophthamol.
2001; 119:709-717). Examples of PPAR-γ agonists and
PPAR-γ/α agonists include, but are not limited to,
thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone,
and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570,
SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297,
NP0110, DRF4158, NN622, G1262570, PNU182716, DRF552926,
2-[(5,7-dipropyl-3-trifluoromethyl-1,2-benzisoxazol-6-yl)oxy]-2-methylpro-
pionic acid (disclosed in U.S. Ser. No. 09/782,856), and
2(R)-7-(3-(2-chloro-4-(4-fluorophenoxy)phenoxy)propoxy)-2-ethylchromane-2-
-carboxylic acid (disclosed in U.S. Ser. No. 60/235,708 and 60/244,697).

[0349] Another embodiment of the instant invention is the use of the
presently disclosed compounds in combination with gene therapy for the
treatment of cancer. For an overview of genetic strategies to treating
cancer see Hall et al (Am. J. Hum. Genet. 61:785-789, 1997) and Kufe et
al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene
therapy can be used to deliver any tumor suppressing gene. Examples of
such genes include, but are not limited to, p53, which can be delivered
via recombinant virus-mediated gene transfer (see U.S. Pat. No.
6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated
Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor
Growth and Dissemination in Mice," Gene Therapy, August 1998;
5(8):1105-13), and interferon gamma (J. Immunol. 2000; 164:217-222).

[0350] The compounds of the instant invention may also be administered in
combination with an inhibitor of inherent multidrug resistance (MDR), in
particular MDR associated with high levels of expression of transporter
proteins. Such MDR inhibitors include inhibitors of p-glycoprotein
(P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833
(valspodar).

[0351] A compound of the present invention may be employed in conjunction
with anti-emetic agents to treat nausea or emesis, including acute,
delayed, late-phase, and anticipatory emesis, which may result from the
use of a compound of the present invention, alone or with radiation
therapy. For the prevention or treatment of emesis, a compound of the
present invention may be used in conjunction with other anti-emetic
agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor
antagonists, such as ondansetron, granisetron, tropisetron, and
zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid
such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide,
Preferid, Benecorten or others such as disclosed in U.S. Pat. Nos.
2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359,
3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines
(for example prochlorperazine, fluphenazine, thioridazine and
mesoridazine), metoclopramide or dronabinol. In another embodiment,
conjunctive therapy with an anti-emesis agent selected from a
neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a
corticosteroid is disclosed for the treatment or prevention of emesis
that may result upon administration of the instant compounds.

[0353] In an embodiment, the neurokinin-1 receptor antagonist for use in
conjunction with the compounds of the present invention is selected from:
2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoropheny-
l)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine, or a
pharmaceutically acceptable salt thereof, which is described in U.S. Pat.
No. 5,719,147.

[0354] A compound of the instant invention may also be administered with
an agent useful in the treatment of anemia. Such an anemia treatment
agent is, for example, a continuous eythropoiesis receptor activator
(such as epoetin alfa).

[0355] A compound of the instant invention may also be administered with
an agent useful in the treatment of neutropenia. Such a neutropenia
treatment agent is, for example, a hematopoietic growth factor which
regulates the production and function of neutrophils such as a human
granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF
include filgrastim.

[0356] A compound of the instant invention may also be administered with
an immunologic-enhancing drug, such as levamisole, isoprinosine and
Zadaxin.

[0359] A compound of the instant invention may also be useful for treating
or preventing cancer, including bone cancer, in combination with
bisphosphonates (understood to include bisphosphonates, diphosphonates,
bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates
include but are not limited to: etidronate (Didronel), pamidronate
(Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate
(Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate,
EB-1053, minodronate, neridronate, piridronate and tiludronate including
any and all pharmaceutically acceptable salts, derivatives, hydrates and
mixtures thereof.

[0360] A compound of the instant invention may also be useful for treating
or preventing breast cancer in combination with aromatase inhibitors.
Examples of aromatase inhibitors include but are not limited to:
anastrozole, letrozole and exemestane.

[0361] A compound of the instant invention may also be useful for treating
or preventing cancer in combination with siRNA therapeutics.

[0367] The compounds of the instant invention are useful for treating
cancer in combination with taxanes.

[0368] The compounds of the instant invention are useful for treating
cancer in combination with docetaxel (Taxotere®).

[0369] The compounds of the instant invention are useful for treating
cancer in combination with vorinostat (Zolinza®).

[0370] The compounds of the instant invention are useful for treating
cancer in combination with the aurora kinase inhibitor, MK-0457.

[0371] The compounds of the instant invention are useful for treating
cancer in combination with the mTOR inhibitor, AP 23573.

[0372] The compounds of the instant invention are useful for treating
cancer in combination with the IGF1R inhibitor, MK-0646.

[0373] The compounds of the instant invention are useful for treating
cancer in combination with satraplatin.

[0374] The compounds of the instant invention are useful for treating
cancer in combination with lapatinib (Tykerb®).

[0375] Thus, the scope of the instant invention encompasses the use of the
instantly claimed compounds in combination with a second compound
selected from: an estrogen receptor modulator, an androgen receptor
modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent,
an antiproliferative agent, a prenyl-protein transferase inhibitor, an
HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse
transcriptase inhibitor, an angiogenesis inhibitor, PPAR-γ
agonists, PPAR-δ agonists, an inhibitor of inherent multidrug
resistance, an anti-emetic agent, an agent useful in the treatment of
anemia, an agent useful in the treatment of neutropenia, an
immunologic-enhancing drug, an inhibitor of cell proliferation and
survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA
therapeutic, γ-secretase inhibitors, agents that interfere with
receptor tyrosine kinases (RTKs), an agent that interferes with a cell
cycle checkpoint and any of the therapeutic agents listed above.

[0376] The term "administration" and variants thereof (e.g.,
"administering" a compound) in reference to a compound of the invention
means introducing the compound or a prodrug of the compound into the
system of the animal in need of treatment. When a compound of the
invention or prodrug thereof is provided in combination with one or more
other active agents (e.g., a cytotoxic agent, etc.), "administration" and
its variants are each understood to include concurrent and sequential
introduction of the compound or prodrug thereof and other agents.

[0377] As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as
well as any product which results, directly or indirectly, from
combination of the specified ingredients in the specified amounts.

[0378] The term "therapeutically effective amount" as used herein means
that amount of active compound or pharmaceutical agent that elicits the
biological or medicinal response in a tissue, system, animal or human
that is being sought by a researcher, veterinarian, medical doctor or
other clinician.

[0379] The term "treating cancer" or "treatment of cancer" refers to
administration to a mammal afflicted with a cancerous condition and
refers to an effect that alleviates the cancerous condition by killing
the cancerous cells, but also to an effect that results in the inhibition
of growth and/or metastasis of the cancer.

[0380] In an embodiment, the angiogenesis inhibitor to be used as the
second compound is selected from a tyrosine kinase inhibitor, an
inhibitor of epidermal-derived growth factor, an inhibitor of
fibroblast-derived growth factor, an inhibitor of platelet derived growth
factor, an MMP (matrix metalloprotease) inhibitor, an integrin blocker,
interferon-α, interleukin-12, pentosan polysulfate, a
cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4,
squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide,
angiostatin, troponin-1, or an antibody to VEGF. In an embodiment, the
estrogen receptor modulator is tamoxifen or raloxifene.

[0381] Also included in the scope of the claims is a method of treating
cancer that comprises administering a therapeutically effective amount of
a compound of the instant invention in combination with radiation therapy
and/or in combination with a second compound selected from: an estrogen
receptor modulator, an androgen receptor modulator, a retinoid receptor
modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a
prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an
HIV protease inhibitor, a reverse transcriptase inhibitor, an
angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an
inhibitor of inherent multidrug resistance, an anti-emetic agent, an
agent useful in the treatment of anemia, an agent useful in the treatment
of neutropenia, an immunologic-enhancing drug, an inhibitor of cell
proliferation and survival signaling, a bisphosphonate, an aromatase
inhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents
that interfere with receptor tyrosine kinases (RTKs), an agent that
interferes with a cell cycle checkpoint and any of the therapeutic agents
listed above.

[0382] And yet another embodiment of the invention is a method of treating
cancer that comprises administering a therapeutically effective amount of
a compound of the instant invention in combination with paclitaxel or
trastuzumab.

[0383] The invention further encompasses a method of treating or
preventing cancer that comprises administering a therapeutically
effective amount of a compound of the instant invention in combination
with a COX-2 inhibitor.

[0384] The instant invention also includes a pharmaceutical composition
useful for treating or preventing cancer that comprises a therapeutically
effective amount of a compound of the instant invention and a second
compound selected from: an estrogen receptor modulator, an androgen
receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic
agent, an antiproliferative agent, a prenyl-protein transferase
inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a
reverse transcriptase inhibitor, an angiogenesis inhibitor, a
PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of cell
proliferation and survival signaling, a bisphosphonate, an aromatase
inhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents
that interfere with receptor tyrosine kinases (RTKs), an agent that
interferes with a cell cycle checkpoint and any of the therapeutic agents
listed above.

[0387] The compounds of this invention may be prepared by employing
reactions as shown in the following Reaction Schemes, in addition to
other standard manipulations that are known in the literature or
exemplified in the experimental procedures. The illustrative Reaction
Schemes below, therefore, are not limited by the compounds listed or by
any particular substituents employed for illustrative purposes.
Substituent numbering as shown in the Reaction Schemes does not
necessarily correlate to that used in the claims and often, for clarity,
a single substituent is shown attached to the compound where multiple
substituents are allowed under the definitions of Formula A hereinabove.

Synopsis of Reaction Schemes

[0388] The following Reaction Schemes, Reaction Schemes I-IV, provide
useful details for preparing the instant compounds. The requisite
intermediates are in some cases commercially available or can be prepared
according to literature procedures.

[0389] As illustrated in Reaction Scheme I, wherein Rp1 and Rp2
are independently H or amino protective group and may be appropriately
deprotected or replaced with other protective groups in the reaction
scheme if necessary, a cycloalkyl(phenyl)acetic acid derivative is first
reacted and rearranged under Curtius-type conditions to give the
cyclobutylamines I-1. Cyanation, in this case catalysed by palladium,
gives nitrile I-2. Reaction of I-2 with a nucleophilic benzyl Grignard
reagent and hydrolytic work-up gives ketone I-3. Condensation of I-3 with
aldehyde I-4 under basic conditions gives the chloronaphthyridine I-5.
Displacement of the chlorine with hydrazine gives hydrazide I-6.
Acylation gives acyl hydrazide I-7 which is cyclized under acidic
conditions gives the triazolonaphthyridine I-8. Deprotection of I-8
generates I-9.

[0390] An alternative triazolonaphthyridine synthesis is outlined in
Reaction Scheme II. In this case the aldehyde I-4 is first condensed with
a phenylacetyl chloride under basic conditions to give the
chloropyridopyrazinol II-1. The intermediate II-1 is then reacted with
hydrazine and coupled with a carboxylic acid in a similar manner used for
the conversion of I-5 to I-7 (Reaction Scheme I), to give the
carbohydrazide II-3. This is cyclized under dehydrating conditions with a
reagent such as phosphorus oxychloride to give the triazolopyridopyrazine
II-4. Intermediate II-4 is then coupled with an appropriately
functionalized benzene derivative, in this case boronic acid derivative,
to give II-5. Deprotection of II-5 gives II-6.

[0391] Compounds of the instant invention may be prepared according to the
procedures outlined in Reaction Scheme III. In this case, diamines III-1
are reacted with a methyl oxo(phenyl)acetate under basic conditions to
give III-2. The intermediate III-2 may then be carried through a similar
sequence of reactions as described for the synthesis of II-6 from II-1
(Reaction Scheme II) to give triazolopyridopyrazine III-7.

[0392] The compound IV-1 was synthesized from the intermediate I-8 by
Dimroth rearrangement and deprotection.

##STR00025## ##STR00026##

##STR00027## ##STR00028##

##STR00029## ##STR00030##

EXAMPLES

[0393] Examples and schemes provided are intended to assist in a further
understanding of the invention. Particular materials employed, species
and conditions are intended to be further illustrative of the invention
and do not limit the reasonable scope thereof.

##STR00031## ##STR00032## ##STR00033##

Ethyl 2-(4-bromophenyl)-4-(chloromethyl)pent-4-enoate (1-1)

[0394] To a solution of ethyl (4-bromophenyl)acetate (143 g, 588 mmol) in
THF (800 mL) was added LHMDS (1.13 eq in THF) at -78° C. After 30
minutes, the reaction mixture was added to a solution of
3-chloro-2-chloromethyl-1-propene (147 g, 1180 mmol) in THF (500 mL) at
-78° C. via cannula. The reaction was allowed to slowly warm from
-78° C. to rt over 15 hours. The reaction mixture was poured into
sodium bicarbonate, extracted with EtOAc, dried over sodium sulfate,
filtered and concentrated. The crude residue was purified by column
chromatography eluting with 1-20% EtOAc/Hexane. The appropriate fractions
were combined and the solvent removed in vacuo to give ethyl
2-(4-bromophenyl)-4-(chloromethyl)pent-4-enoate (1-1) as a clear oil. MS
(M+H).sup.+: 332.

Ethyl 2-(4-bromophenyl)-5-chloro-4-oxopentanoate (1-2)

[0395] Through a solution of ethyl
2-(4-bromophenyl)-4-(chloromethyl)pent-4-enoate

[0396] (1-1) (7.3 g, 25 mmol) in methanol (40 mL) and CH2Cl2 (40
mL) at -78° C. was bubbled O3 until the reaction turned
slightly blue (6 hours). The reaction was allowed to stir for an
additional 1 hour, at which time N2 gas was bubbled through the
reaction mixture until the solution was colorless. Excess methyl sulfide
(3.75 g, 60.3 mmol) was added to the reaction and the mixture was allowed
to warm from -78° C. to rt. The reaction mixture was poured into
saturated sodium bicarbonate, extracted with DCM, dried over sodium
sulfate filtered and concentrated. The crude residue was purified by
column chromatography eluting with 1-20% EtOAc/Hexane. The appropriate
fractions were combined and the solvent removed in vacuo to give ethyl
2-(4-bromophenyl)-5-chloro-4-oxopentanoate (1-2) as a solid. MS
(M+H).sup.+: 153.

[0397] To a solution of ethyl 2-(4-bromophenyl)-5-chloro-4-oxopentanoate
(1-2) (35 g, 105 mmol) and ethylene glycol (19.5 g, 315 mmol) in toluene
(300 mL) was added para-toluenesulfonic acid (100 mg) and the reaction
was heated to reflux with a dean stark trap for 6 hours. The reaction
mixture was concentrated was purified by column chromatography eluting
with 0-50% EtOAc/Hexane. The appropriate fractions were combined,
concentrated, and the resulting solid was recrystallized from EtOAc and
hexane to give ethyl
2-(4-bromophenyl)-3-[2-(chloromethyl)-1,3-dioxolan-2-yl]propanoate (1-3)
as a white solid MS (M+H).sup.+: 378.

2-(4-Bromophenyl)-5,8-dioxaspiro[3.4]octane-2-carboxylic acid (1-4)

[0398] To a solution of ethyl
2-(4-bromophenyl)-3-[2-(chloromethyl)-1,3-dioxolan-2-yl]propanoate (1-3)
(27 g, 71.5 mmol) cooled to -78° C. in DMF (200 mL) was added NaH
(8.58 g, 214 mmol) and the reaction was allowed to slowly warm from
-78° C. to rt. Once at rt, 1N NaOH (100 mL) was added and the
reaction mixture was stirred over night. The crude reaction mixture was
poured into saturated sodium bicarbonate and washed with chloroform. The
aqueous layer was acidified with HCl, extracted with chloroform, dried
over sodium sulfate filtered and concentrated. The crude residue was
purified by column chromatography eluting with 1-50% EtOAc/Hexane. The
appropriate fractions were concentrated and recrystallized from
EtOAc/hexane to give
2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octane-2-carboxylic acid (1-4) as a
white solid. MS (M+H).sup.+: 314.

[0410] To a micro reactor vessel was added
(2-(1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo[3,4-f]-1,-
6-naphthyridin-8-yl]phenyl}-3-oxocyclobutyl)-1H-isoindole-1,3(2H)-dione
(1-13) (100 mg, 0.162 mmol), TFA (1 mL), and MeOH (5 mL), and the mixture
was heated under microwave irradiation at 100° C. for 10 minutes.
Then hydrazine hydrate (80 mg, 1.6 mmol) was added, and the mixture was
heated under microwave irradiation at 100° C. for 10 minutes. The
solvent was concentrated under reduced pressure, and the residue was
purified by reverse phase column chromatography (Sunfire C18) eluting
with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The appropriate
fractions were free based by suspending in ethyl acetate, washed with a
saturated solution of sodium bicarbonate, followed by water, brine, dried
over sodium sulfate, filtered, and concentrated in vacuo to give
3,3-dimethoxy-1-{4-[3-(1-methyl-1H-imidazol-4-yl)-9-phenyl[1,2,4]triazolo-
[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutanamine (1-18). HRMS
(M+H).sup.+: observed=532.2461, calculated=532.2466.

[0411] To a solution of tert-butyl
(2-chloro-3-formyl-4-pyridinyl)carbamate (10 g, 39 mmol) and DBU (11.7
mL, 78 mmol) in THF (130 mL) was added phenylacetyl chloride (5.7 mL, 43
mmol) at 0° C. The reaction was allowed to slowly warm to room
temperature for overnight. The solvent was removed under reduced
pressure, and the residue was diluted with EtOAc, washed with 1N HCl,
dried (MgSO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel to give
tert-butyl 5-chloro-2-oxo-3-phenyl-1,6-naphthyridine-1(2H)-carbamate
(2-2) as a colorless solid.

5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3)

[0412] A mixture of tert-butyl
5-chloro-2-oxo-3-phenyl-1,6-naphthyridine-1(2H)-carbamate (2-2) (2.0 g,
5.6 mmol) and hydrazine hydrate (7.2 g, 112 mmol) in 1,4-dioxane (28 mL)
was heated under microwave irradiation at 120° C. for 20 minutes.
The solvent was removed under reduced pressure, and water was added to
the residue. The resulting solid was collected by filtration to give
5-hydrazino-3-phenyl-1,6-naphthyridine-2(1H)-one (2-3) as a colorless
solid.

[0414] To a solution of
9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8(7H)-o-
ne (2-4) (1.4 g, 4.1 mmol) and DMF (0.032 mL) in acetonitrile (20 mL) was
added POCl3 (2.3 mL, 24.6 mmol). After stirring at 120° C.
for overnight, the solvent was removed under reduced pressure, and the
residue was diluted with acetonitrile, and added water. The resulting
solid was collected by filtration to give
8-chloro-9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridi-
ne (2-5) as a colorless solid.

[0434] To a mixture of
N'-(2-hydroxy-3-phenylpyrido[2,3-b]pyrazin-6-yl)nicotinohydrazide (3-4)
(5.8 g, 16.2 mmol) in acetonitrile (1.3 mL) was added POCl3 (7.5 mL,
81 mmol), and stirred at 100° C. for overnight. The solvent was
removed under reduced pressure, and to the residue was added CHCl3
and water. The organic layer was separated, dried (Na2SO4),
filtered, and evaporated in vacuo. To the residue was added CHCl3,
and the resulting solid was collected by filtration to yield
3-chloro-2-phenyl-9-(3-pyridinyl)[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]p-
yrazine (3-5) as an orange solid.

[0478] To a mixture of
2,2,2-trifluoro-N-(2-{9-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-
-1,6-naphthyridin-8-yl]phenyl}-5,8-dioxaspiro[3.4]oct-2-yl)acetamide (44)
(620 mg, 0.99 mmol) in acetone (15 mL) was added 1N HCl (8 mL, 8.00
mmol), and the mixture was stirred at 80° C. for 2 days. The
precipitate was collected by filtration and washed with water to give
2,2,2-trifluoro-N-(3-oxo-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo-
[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) as a
colorless solid.

[0481] To a mixture of
N-(3-(dimethylamino)-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-
-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide
(4-4) (10 mg, 0.016 mmol) in EtOH (1.0 mL) was added KOH (1M in water,
0.1 mL, 0.10 mmol), and the mixture was heated under microwave
irradiation at 100° C. for 40 minutes. To the mixture was added
EtOAc, sat. NaHCO3, and brine. The resulting solid was collected by
filtration to give
N3,N3-dimethyl-1-{4-[9-phenyl-3-(2-pyrimidinyl)-[1,2,4]triazolo-
[3,4-f]-1,6-naphthyridin-8-yl]phenyl}-1,3-cyclobutanediamine (4-5) as
colorless solid. HRMS (M+H).sup.+: observed=513.2515,
calculated=513.2510.

[0482] The following compound was prepared in a similar fashion to Example
4-5, but using the appropriate starting materials: [0483]
N3-methyl-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-
-naphthyridin-8-yl]phenyl}-1,3-cyclobutanediamine (4-6). HRMS (M+H).sup.+:
observed=499.2359, calculated=499.2352.

[0484] To a mixture of
2,2,2-trifluoro-N-(3-oxo-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo-
[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (69 mg,
0.119 mmol) in CHCl3 (2.5 mL) was added
[bis(2-methoxymethyl)amino]sulfur trifluoride (0.066 mL, 0.357 mmol), and
the mixture was heated under microwave irradiation at 130° C. for
30 minutes. The solvent was removed under reduced pressure, and the
residue was purified by reverse phase column chromatography (Sunfire C18)
eluting with 5 to 95% acetonitrile/(0.1% TFA/water) gradient. The
appropriate fractions were free based by suspending in ethyl acetate,
washed with a saturated solution of sodium bicarbonate, followed by
water, brine, dried over sodium sulfate, filtered, and concentrated in
vacuo to give
N-(3,3-difluoro-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1-
,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-7) as
colorless solid. MS (M+H).sup.+: observed=602, calculated=602.

[0488] A mixture of methyl(triphenyl)phosphonium bromide (111 mg, 0.311
mmol) and potassium tert-butoxide (35 mg, 0.311 mmol) in 1,4-dioxane (2
mL) was stirred at 30° C. for 30 minutes.
2,2,2-trifluoro-N-(3-oxo-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo-
[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (60 mg,
0.104 mmol) in 1,4-dioxane (2 mL) was added, and the mixture was stirred
at room temperature for 15 hours. To the mixture was added NH4Cl,
extracted with EtOAc, washed with water and brine, dried (MgSO4),
filtered, and the solvent was removed under reduced pressure. The residue
was purified by column chromatography eluting with 0-10% methanol in
CHCl3 to give
2,2,2-trifluoro-N-(3-methylene-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]tr-
iazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-11) as
a white solid.

[0489] A mixture of
2,2,2-trifluoro-N-(3-methylene-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]tr-
iazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-11) (5
mg, 0.009 mmol) and palladium on carbon (10%, 10 mg) in THF (5 mL) was
stirred under H2 atmosphere at room temperature for 30 minutes. The
mixture was filtered through celite pad and the solvent was removed under
reduced pressure. The residue was purified by preparative TLC eluting
with 5% EtOAc in hexane to give
2,2,2-trifluoro-N-(3-methyl-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazo-
lo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-12) as a
white solid.

[0490] A mixture of
2,2,2-trifluoro-N-(3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triaz-
olo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-12) (3.3
mg, 0.006 mmol) and NaOH (5M in water, 0.30 mL) in EtOH (3 mL) was
stirred at 70° C. for 15 hours. The mixture was diluted with
CHCl3, washed with water and brine, dried (MgSO4), filtered,
and the solvent was removed under reduced pressure. The residue was
purified by preparative TLC eluting with 10% MeOH in CHCl3 to give
3-methyl-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naph-
thyridin-8-yl]phenyl}cyclobutanamine (4-13) as a white form. HRMS
(M+H).sup.+: observed=484.2250, calculated=484.2243.

[0499] This compound was synthesized in a manner similar to the procedure
in Scheme 1, but using the appropriate starting materials such as the
compound 5-7. HRMS (M+H).sup.+: observed=508.2061, calculated=508.2059.

[0507] To a mixture of
{1-[4-(3-amino-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl)pheny-
l]-3,3-difluorocyclobutyl}carbamate (5-18) (4 mg, 0.007 mmol) in
CHCl3 (0.5 mL) was added TFA (0.5 mL), and the mixture was stirred
at room temperature for 1 hour. The solvent was concentrated under
reduced pressure and the residue was purified by reverse phase column
chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1%
TFA/water) gradient. The appropriate fractions were free based by
suspending in ethyl acetate, washed with a saturated solution of sodium
bicarbonate, followed by water, brine, dried over sodium sulfate,
filtered, and concentrated in vacuo to give
8-[4-(1-amino-3,3-difluorocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4--
f]-1,6-naphthyridin-3-amine (5-19) as a yellow oil. HRMS (M+H).sup.+:
observed=443.1796, calculated=443.1801.

[0509] To a mixture of tert-butyl
{3,3-difluoro-1-[4-(3-hydroxy-9-phenyl[1,2,4]triazolo[3,4-f]-1,6-naphthyr-
idin-8-yl)phenyl]cyclobutyl}carbamate (5-20) (11 mg, 0.021 mmol) in
CHCl3 (0.5 mL) was added TFA (0.5 mL), and the mixture was stirred
at room temperature for 1 hour. The solvent was concentrated under
reduced pressure and the residue was purified by reverse phase column
chromatography (Sunfire C18) eluting with 5 to 95% acetonitrile/(0.1%
TFA/water) gradient. The appropriate fractions were free based by
suspending in ethyl acetate, washed with a saturated solution of sodium
bicarbonate, followed by water, brine, dried over sodium sulfate,
filtered, and concentrated in vacuo to give
8-[4-(1-amino-3,3-difluorocyclobutyl)phenyl]-9-phenyl[1,2,4]triazolo[3,4--
f]-1,6-naphthyridin-3-ol (5-21) as a yellow oil. HRMS (M+H).sup.+:
observed=444.1636, calculated=444.1653.

[0512] A mixture of 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octan-2-amine
(7-1) (2.7 g, 9.50 mmol), ethyl
1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate (4.2 g, 19.0 mmol), and
TEA (5.3 mL, 38.0 mmol) in CHCl3 (50 mL) was stirred at 70°
C. for overnight. The solvent was evaporated under reduced pressure, and
to the residue was added MeOH. The resulting solid was collected by
filtration to give
2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-di-
one (7-2) as a colorless solid.

[0516] This compound was prepared in a same manner to example 7-6, but
using 2-[cis-1-(4-bromophenyl)-3-hydroxy-3-methylcyclobutyl]-1H-isoindole-
-1,3(2H)-dione (7-5) as a starting material.

[0517] The following compounds were prepared in a similar fashion to
Example 7-6, but using the appropriate starting materials: [0518]
2-{trans-3-cyclopropyl-3-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxabor-
olan-2-yl)phenyl]cyclobutyl}-1H-isoindole-1,3(2H)-dione (7-8); and [0519]
2-{cis-3-cyclopropyl-3-hydroxy-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-
an-2-yl)phenyl]cyclobutyl}-1H-isoindole-1,3(2H)-dione (7-9).

[0520] To a solution of
2-[1-(4-bromophenyl)-3-oxocyclobutyl]-1H-isoindole-1,3(2H)-dione (7-3)
(216 mg, 0.583 mmol) in THF (2 mL) was added L-selectride (1M in THF,
0.59 mL, 0.59 mmol) at -78° C. After stirring 45 minutes, the
reaction was quenched by sat. aq. NH4Cl, and the mixture was
extracted with EtOAc. The combined organic fractions were dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by silica gel chromatography, eluting with
0˜100% EtOAc in hexane, to give
2-[trans-1-(4-bromophenyl)-3-hydroxycyclobutyl]-1H-isoindole-1,3(2H)-dion-
e (7-10) as a colorless solid.

[0521] To a solution of
2-[trans-1-(4-bromophenyl)-3-hydroxycyclobutyl]-1H-isoindole-1,3(2H)-dion-
e (7-8) (162 mg, 0.435 mmol) in CHCl3 (2 mL) was added
bis(methoxyethyl)amino sulfur trifluoride (0.09 mL, 0.522 mmol), and the
mixture was stirred at room temperature for 1 hour. The reaction was
quenched by sat. aq. NaHCO3, and the mixture was extracted with
EtOAc. The combined organic fractions were dried (MgSO4), filtered,
and concentrated under reduced pressure. The residue was purified by
silica gel chromatography, eluting with 0˜100% EtOAc in hexane, to
give 2-[cis-1-(4-bromophenyl)-3-fluorocyclobutyl]-1H-isoindole-1,3(2H)-di-
one (7-11) as a colorless oil.

[0529] To a mixture of 6-hydrazino-3-phenylpyrido[2,3-b]pyrazin-2-ol (3-3)
(200 mg, 0.79 mmol) and DIEA (0.55 mL, 3.16 mmol) in NMP (8 mL) was added
morpholine-4-carbonyl chloride (354 mg, 2.37 mmol), and stirred at room
temperature for 1 hour. To the mixture was added water and Et2O, and
the precipitate was collected by filtration to yield
N'-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)morpholine-4-carb-
ohydrazide (8-1) as a pale yellow solid.

[0530] A mixture of
N'-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)morpholine-4-carb-
ohydrazide (8-1) (165 mg, 0.450 mmol) and phosphorus oxychloride (5 mL)
was stirred at 150° C. for 6 h. The solvent was removed under
reduced pressure, and to the residue was added CHCl3 and sat. aq.
NaHCO3. The organic layer was separated, dried (MgSO4),
filtered, and evaporated in vacuo. The residue was purified by column
chromatography eluting with 0-5% MeOH/CHCl3. The appropriate
fractions were combined and the solvent removed in vacuo to give
3,9-dichloro-2-phenyl[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]pyrazine
(8-2) as a pale yellow foam.

[0542] To a mixture of 6-hydrazinyl-3-phenylpyrido[2,3-b]pyrazin-2(1H)-one
(3-3) (300 mg, 1.19 mmol), HOBt (218 mg, 1.42 mmol) and oxamic acid (130
mg, 1.42 mmol) in NMP (12 mL) was added EDC (272 mg, 1.42 mmol) at room
temperature and the mixture was stirred for 30 min. After addition of TFA
(0.091 mL, 1.19 mmol), the mixture was heated under microwave irradiation
at 150° C. for 30 minutes. To a mixture was added water (60 mL)
and the precipitate was collected by filtration to give
3-hydroxy-2-phenyl[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]pyrazin-9-carbox-
amide (9-1) as a yellow powder.

[0545] A mixture of
3-{-4-[trans-3-cyclopropyl-1-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-h-
ydroxycyclobutyl]phenyl}-2-phenyl[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]py-
razine-9-carboxamide (9-3) (40 mg, 0.064 mmol) and hydrazine hydrate (50
mg, 1.0 mmol) in EtOH (1 mL) was stirred at 50° C. for 30 minutes.
The solvent was evaporated in vacuo, and the residue was diluted with
EtOH (1 mL) and stirred at 130° C. for 30 minutes. The solvent was
removed under reduced pressure, and the residue was diluted with
CHCl3/IPA, washed with sat. aq. NaHCO3 and brine, dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography eluting with 0-20%
MeOH/CHCl3. The appropriate fractions were combined and the solvent
removed in vacuo to give
3-[4-(trans-1-amino-3-cyclopropyl-3-hydroxycyclobutyl)phenyl]-2-phenyl[1,-
2,4]triazolo[4',3'; 1,6]pyrido[2,3-b]pyrazin-9-carboxamide (9-4). MS
(M+H).sup.+: observed=492, calculated=492.

[0547] To a mixture of 6-hydrazinyl-3-phenylpyrido[2,3-b]pyrazin-2(1H)-one
(3-3) (300 mg, 1.19 mmol) in CHCl3 (20 mL) and pyridine (10 mL) was
added chloroacetic anhydride (304 mg, 1.78 mmol). After stirring for 30
min, the solvent was removed under reduced pressure. The residue was
dissolved in MeOH and then water was added. The precipitate was collected
by filtration to give
2-chloro-N'-(2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)acetohyd-
razide (10-1) as a colorless solid.

[0551] This compound was prepared in a similar manner to the procedure to
describe in scheme 4, but using the appropriate starting materials. MS
(M+H).sup.+: observed=506, calculated=506.

[0552] The following compound was prepared in a similar fashion to Example
10-5, but using the appropriate starting materials: [0553]
N-({3-[4-(trans-1-amino-3-cyclopropyl-3-hydroxycyclobutyl)phenyl]-2-pheny-
l[1,2,4]triazolo[4',3':1,6]pyrido[2,3-b]pyrazin-9-yl}methyl)acetamide
(10-6) MS (M+H).sup.+: observed=520, calculated=520.

[0554] To a mixture of 6-hydrazinyl-3-phenylpyrido[2,3-b]pyrazin-2(1H)-one
(3-3) (500 mg, 1.97 mmol) in DMF (10 mL) and pyridine (10 mL) was added
methyl chloroglyoxylate (290 mg, 2.37 mmol). After stirring for 30 min,
the solvent was removed under reduced pressure. The residue was dissolved
in MeOH and then water was added. The precipitate was collected by
filtration to give methyl
oxo[2-oxo-3-phenyl-1,2-dihydropyrido[2,3-b]pyrazin-6-yl)hydrazinyl]acetat-
e (11-1).

[0558] The pS2neo vector (deposited in the ATCC on Apr. 3, 2001 as ATCC
PTA-3253) was prepared as follows: The pRmHA3 vector (prepared as
described in Nucl. Acid Res. 16:1043-1061 (1988)) was cut with BglII and
a 2734 bp fragment was isolated. The pUChsneo vector (prepared as
described in EMBO J. 4:167-171 (1985)) was also cut with BglII and a 4029
bp band was isolated. These two isolated fragments were ligated together
to generate a vector termed pS2neo-1. This plasmid contains a polylinker
between a metallothionine promoter and an alcohol dehydrogenase poly A
addition site. It also has a neo resistance gene driven by a heat shock
promoter. The pS2neo-1 vector was cut with Psp5II and BsiWI. Two
complementary oligonucleotides were synthesized and then annealed
(CTGCGGCCGC (SEQ. ID. NO.: 1) and GTACGCGGCCGCAG (SEQ. ID. NO.: 2)). The
cut pS2neo-1 and the annealed oligonucleotides were ligated together to
generate a second vector, pS2neo. Added in this conversion was a NotI
site to aid in the linearization prior to transfection into S2 cells.

[0559] Human Akt1 gene was amplified by PCR (Clontech) out of a human
spleen cDNA (Clontech) using the 5' primer:
5'CGCGAATTCAGATCTACCATGAGCGACGTGGCTATTGTG 3' (SEQ. ID. NO.: 3), and the
3' primer: 5'CGCTCTAGAGGATCCTCAGGCCGTGCTGCTGGC3' (SEQ. ID. NO.: 4). The
5' primer included an EcoRI and BglII site. The 3' primer included an
XbaI and BamHI site for cloning purposes. The resultant PCR product was
subcloned into pGEM3Z (Promega) as an EcoRI/Xba I fragment. For
expression/purification purposes, a middle T tag was added to the 5' end
of the full length Akt1 gene using the PCR primer:
5'GTACGATGCTGAACGATATCTTCG 3' (SEQ. ID. NO.: 5). The resulting PCR
product encompassed a 5' KpnI site and a 3' BamHI site which were used to
subclone the fragment in frame with a biotin tag containing insect cell
expression vector, pS2neo.

[0560] For the expression of a pleckstrin homology domain (PH) deleted
(Δaa 4-129, which includes deletion of a portion of the Akt1 hinge
region) version of Akt1, PCR deletion mutagenesis was done using the full
length Akt1 gene in the pS2neo vector as template. The PCR was carried
out in 2 steps using overlapping internal primers
(5'GAATACATGCCGATGGAAAGCGACGGGGCTGAAGAGATGGAGGTG 3' (SEQ. ID. NO.: 6),
and 5'CCCCTCCATCTCTTCAGCCCCGTCGCTTICCATCGGCATG TATTC 3' (SEQ. ID. NO.:
7)) which encompassed the deletion and 5' and 3' flanking primers which
encompassed the KpnI site and middle T tag on the 5' end. The final PCR
product was digested with KpnI and SmaI and ligated into the pS2neo full
length Akt1 KpnI/SmaI cut vector, effectively replacing the 5' end of the
clone with the deleted version.

These primers included a 5' EcoRI/BglII site and a 3' XbaI/BglII site for
cloning purposes. The resultant PCR product was cloned into the EcoRI and
XbaI sites of pGEM4Z (Promega). For expression/purification purposes, a
middle T tag was added to the 5' end of the full length Akt3 clone using
the PCR primer: 5'GGTACCATGGAATACATGCCGATGGAAAGCGATGTTACCATTGTGAAG
3'(SEQ. ID. NO.: 10). The resultant PCR product encompassed a 5' KpnI
site which allowed in frame cloning with the biotin tag containing insect
cell expression vector, pS2neo.

[0562] Human Akt2 gene was amplified by PCR from human thymus cDNA
(Clontech) using the amino terminal oligo primer: 5'
AAGCTTAGATCTACCATGAATGAGGTGTCTGTC 3' (SEQ. ID. NO.: 11); and the carboxy
terminal oligo primer: 5'GAATTCGGATCCTCACTCGCGGATGCTGGC 3' (SEQ. ID. NO.:
12). These primers included a 5' HindIII/BglII site and a 3' EcoRI/BamHI
site for cloning purposes. The resultant PCR product was subcloned into
the HindIII/EcoRI sites of pGem3Z (Promega). For expression/purification
purposes, a middle T tag was added to the 5' end of the full length Akt2
using the PCR primer: 5'GGTACCATGGAATACATGCCGATGGAAAATGAGGTGTCTGTCATCAAAG
3' (SEQ. ID. NO.: 13). The resultant PCR product was subcloned into the
pS2neo vector as described above.

Example 2

Expression of Human Akt Isoforms and Delta-PH-Akt1

[0563] The DNA containing the cloned Alai, Akt2, Akt3 and delta-PH-Akt1
genes in the pS2neo expression vector was purified and used to transfect
Drosophila S2 cells (ATCC) by the calcium phosphate method. Pools of
antibiotic (G418, 500 μg/mL) resistant cells were selected. Cell were
expanded to a 1.0 L volume (˜7.0×106/mL), biotin and
CuSO4 were added to a final concentration of 50 μM and 50 mM
respectively. Cells were grown for 72 h at 27° C. and harvested by
centrifugation. The cell paste was frozen at -70° C. until needed.

[0566] Activated Akt isoforms and pleckstrin homology domain deletion
constructs were assayed utilizing a GSK-derived biotinylated peptide
substrate. The extent of peptide phosphorylation was determined by
Homogeneous Time Resolved Fluorescence (HTRF) using a lanthanide
chelate(Lance)-coupled monoclonal antibody specific for the
phosphopeptide in combination with a streptavidin-linked allophycocyanin
(SA-APC) fluorophore which will bind to the biotin moiety on the peptide.
When the Lance and APC are in proximity (i.e. bound to the same
phosphopeptide molecule), a non-radiative energy transfer takes place
from the Lance to the APC, followed by emission of light from APC at 665
nm.

[0569] The reaction is assembled by adding 16 pt of the ATP/MgCl2
working solution to the appropriate wells of a 96-well microtiter plate.
Inhibitor or vehicle (1.0 μL) is added followed by 10 μL of peptide
working solution. The reaction is started by adding 13 μl, of the
enzyme working solution and mixing. The reaction is allowed to proceed
for 50 min and then stopped by the addition of 60 μL, HTRF quench
buffer. The stopped reactions were incubated at room temperature for at
least 30 min and then read on the Discovery instrument.

[0570] IC50 of example compounds to Akt1 kinase and Akt2 kinase are
shown in the table below.

[0572] The reaction was stopped by adding 170 μL of 125 mM EDTA. 200
μL of stopped reaction was transferred to a Streptavidin
Flashplate® PLUS (NEN Life Sciences, catalog no. SMP103). The plate
was incubated for ≧10 minutes at room temperature on a plate
shaker. The contents of each well was aspirated, and the wells rinsed 2
times with 200 μL TBS per well. The wells were then washed 3 times for
5 minutes with 200 μL TBS per well with the plates incubated at room
temperature on a platform shaker during wash steps.

[0573] The plates were covered with sealing tape and counted using the
Packard TopCount with the appropriate settings for counting [33P] in
Flashplates.

Procedure for Streptavidin Filter Plate Assay:

Step 1:

[0574] The enzymatic reactions as described in Step 1 of the Streptavidin
Flash Plate Assay above were performed.

Step 2:

[0575] The reaction was stopped by adding 20 μL of 7.5M Guanidine
Hydrochloride. 50 μL of the stopped reaction was transferred to the
Streptavidin filter plate (SAM2® Biotin Capture Plate, Promega,
catalog no. V7542) and the reaction was incubated on the filter for 1-2
minutes before applying vacuum.

[0576] The plate was then washed using a vacuum manifold as follows: 1)
4×200 μL/well of 2M NaCl; 2) 6×200 μL/well of 2M NaCl
with 1% H3PO4; 3) 2×200 μL/well of diH2O; and 4)
2×100 pt/well of 95% Ethanol. The membranes were then allowed to
air dry completely before adding scintillant.

[0577] The bottom of the plate was sealed with white backing tape, 30
pt/well of Microscint 20 (Packard Instruments, catalog no. 6013621) was
added. The top of the plate was sealed with clear sealing tape, and the
plate then counted using the Packard TopCount with the appropriate
settings for [33P] with liquid scintillant.

Procedure for Phosphocellulose Filter Plate Assay:

Step 1:

[0578] The enzymatic reactions were performed as described in Step 1 of
the Streptavidin Flash Plate Assay (above) utilizing KKGGRARTSSFAEPG
(SEQ. ID. NO.: 16) as the substrate in place of biotin-GGRARTSSFAEPG.

[0580] The plate was then washed using a vacuum manifold as follows: 1)
9×200 μL/well of 0.75% H3PO4; and 2) 2×200
μL/well of diH20. The bottom of the plate was sealed with white
backing tape, then 30 pt/well of Microscint 20 was added. The top of the
plate was sealed with clear sealing tape, and the plate counted using the
Packard TopCount with the appropriate settings for [33P] and liquid
scintillant.

[0582] The reaction is assembled in a 96 deep-well assay plate. The
inhibitor or vehicle (10 μL) is added to 10 μL of the 33P-ATP
solution. The reaction is initiated by adding 30 μL of the
PKA/Kemptide working solution to each well. The reactions were mixed and
incubated at room temperature for 20 min. The reactions were stopped by
adding 50 μL of 100 mM EDTA and 100 mM sodium pyrophosphate and
mixing.

[0583] The enzyme reaction product (phosphorylated Kemptide) was collected
on p81 phosphocellulose 96 well filter plates (Millipore). To prepare the
plate, each well of a p81 filter plate was filled with 75 mM phosphoric
acid. The wells were emptied through the filter by applying a vacuum to
the bottom of the plate. Phosphoric acid (75 mM, 170 μL) was added to
each well. A 30 μL aliquot from each stopped PKA reaction was added to
corresponding wells on the filter plate containing the phosphoric acid.
The peptide was trapped on the filter following the application of a
vacuum and the filters were washed 5 times with 75 mM phosphoric acid.
After the final wash, the filters were allowed to air dry. Scintillation
fluid (30 μL) was added to each well and the filters counted on a
TopCount (Packard).

[0585] The assays were assembled in 96 deep-well assay plates. Inhibitor
or vehicle (10 μL) was added to 5.0 μl, of 33P-ATP. Reactions
were initiated with the addition of the PKC/Myelin Basic Protein working
solution and mixing. Reactions were incubated at 30° C. for 20
min. The reactions were stopped by adding 50 μL of 100 mM EDTA and 100
mM sodium pyrophosphate and mixing. Phosphorylated Myelin Basic Protein
was collected on PVDF membranes in 96 well filter plates and quantitated
by scintillation counting.

[0586] Compounds of the instant invention described in the Schemes and
Tables were tested in the assay described above and were found to have
IC50 of ≦50 μM against one or more of Akt1, Akt2 and Akt3.

Example 5

Cell Based Assays to Determine Inhibition of Akt/PKB

[0587] Cells (for example LnCaP or a PTEN(-/-) tumor cell line with
activated Akt/PKB) were plated in 100 mm dishes. When the cells were
approximately 70 to 80% confluent, the cells were refed with 5 mLs of
fresh media and the test compound added in solution. Controls included
untreated cells, vehicle treated cells and cells treated with either
LY294002 (Sigma) or wortmanin (Sigma) at 20 μM or 200 nM,
respectively. The cells were incubated for 2, 4 or 6 hrs, and the media
removed, the cells were washed with PBS, scraped and transferred to a
centrifuge tube. They were pelleted and washed again with PBS. Finally,
the cell pellet was resuspended in lysis buffer (20 mM Tris pH8, 140 mM
NaCl, 2 mM EDTA, 1% Triton X-100, 1 mM Na Pyrophosphate, 10 mM
beta-Glycerol Phosphate, 10 mM NaF, 0.5 mm NaVO4, 1 μM
Microsystine, and 1× Protease Inhibitor Cocktail), placed on ice
for 15 minutes and gently vortexed to lyse the cells. The lysate was spun
in a Beckman tabletop ultra centrifuge at 100,000×g at 4° C.
for 20 min. The supernatant protein was quantitated by a standard
Bradford protocol (BioRad) and stored at -70° C. until needed.

[0590] MCF7 cells (a human breast cancer line that is PTEN.sup.+/+) were
plated at 1×106 cells per 100 mM plate. When the cells were
70-80% confluent, they were refed with 5 mL of serum free media and
incubated overnight. The following morning, compound was added and the
cells were incubated for 1-2 hrs, after which time heregulin was added
(to induce the activation of Akt) for 30 minutes and the cells were
analyzed as described above.

Example 7

Inhibition of Tumor Growth

[0591] In vitro/in vivo efficacy of an inhibitor of the growth of cancer
cells may be confirmed by several protocols well known in the art.

[0592] In vitro, 2000-6000 cells/well are seeded into triplicate wells in
96 well plate in complete medium (RPMI-1640 supplemented with 10%
heat-inactivated fetal bovine serum (FBS)) and incubated at 37°
C./5% CO2 overnight. The next day, inhibitors are added as a
dilution series in complete medium (final DMSO concentration in the assay
is 0.1%). The plates are incubated at 37° C./5% CO2 for 72-96
hours. The number of viable cells is then measured using the
CellTiter-Glo kit (Promega). The luminescence signals are measured using
ARVO/Victor 3 plate reader (Perkin-Elmer). The data are fitted with a
four parameter dose-response equation and the inflection point of the
least square fit curve or concentration at 50% inhibition is determined
as an IC50 value.

[0593] In vivo, human tumor cell lines which exhibit a deregulation of the
PI3K pathway (such as LnCaP, PC3, C33a, OVCAR-3, MDA-MB-468, A2780 or the
like) are injected subcutaneously into the left flank of 6-10 week old
female nude (also male mice [age 10-14 weeks] are used for prostate tumor
xenografts [LnCaP and PC3]) mice (Harlan), or female nude rats (F344/N
Jcl-rnu) (CLEA Japan) on day 0. The mice or rats are randomly assigned to
a vehicle, compound or combination treatment group. Daily or every other
day subcutaneous or oral administration begins on day 1 and continues for
the duration of the experiment. Alternatively, the inhibitor test
compound may be administered by a continuous infusion pump. Compound,
compound combination or vehicle is delivered in a total volume of 0.2 mL.
Tumors are excised and weighed when all of the vehicle-treated animals
exhibited lesions of 0.5-1.0 cm in diameter, typically 4 to 5.5 weeks
after the cells were injected. The average weight of the tumors in each
treatment group for each cell line is calculated.

Example 8

Spot Multiplex Assay

[0594] This procedure describes a sandwich immunoassay used to detect
multiple phosphorylated proteins in the same well of a 96 well format
plate. Cell lysates are incubated in 96-well plates on which different
capture antibodies are placed on spatially distinct spots in the same
well. Phosphorylation-specific rabbit polyclonal antibodies are added and
the complex is detected by an anti-rabbit antibody labeled with an
electrochemiluminescent tag.

[0598] This procedure describes a cell-based (in vivo) activity assay for
the Akt serine/threonine kinase. Activated endogenous Akt is capable of
phosphorylating specific Akt substrate (GSK3β) peptide which is
biotinylated. Detection is performed by Homogeneous Time Resolved
Fluorescence (HTRF) using a Europium Kryptate [Eu(K)] coupled antibody
specific for the phosphopeptide and streptavidin linked XL665 fluorophore
which will bind to the biotin moiety on the peptide. When the [Eu(K)] and
XL665 are in proximity (i.e. bound to the same phosphopeptide molecule) a
non-radiative energy transfer takes place from the Eu(K) to the XL665,
followed by emission of light from XL665 at 665 nm.

[0599] The assay can be used to detect inhibitors of all three Akt
isozymes (Akt1, Akt2, and Akt3) from multiple different species if
specific antibodies to each exist.